University of Groningen
The impact of genotoxic stress on protein homeostasis
Huiting, Wouter
DOI:
10.33612/diss.168249330
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2021
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Huiting, W. (2021). The impact of genotoxic stress on protein homeostasis: a study on an emerging theme
and its relevance for age-related degeneration. University of Groningen.
https://doi.org/10.33612/diss.168249330
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CHAPTER 1
1. de Bont, R. Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis 19, 169–185 (2004).
2. Tubbs, A. & Nussenzweig, A. Endogenous DNA Damage as a Source of Genomic Instability in Cancer. Cell 168, 644–656 (2017).
3. Bauer, N. C., Corbett, A. H. & Doetsch, P. W. The current state of eukaryotic DNA base damage and repair. Nucleic Acids Research gkv1136 (2015) doi:10.1093/nar/gkv1136.
4. Alizadeh, E., Orlando, T. M. & Sanche, L. Biomolecular Damage Induced by Ionizing Radiation: The Direct and Indirect Effects of Low-Energy Electrons on DNA. Annual Review of Physical Chemistry 66, 379–398 (2015).
5. Ravanat, J.-L., Douki, T. & Cadet, J. Direct and indirect effects of UV radiation on DNA and its components. Journal of Photochemistry and Photobiology B: Biology 63, 88–102 (2001). 6. Swenberg, J. A. et al. Endogenous versus
Exogenous DNA Adducts: Their Role in Carcinogenesis, Epidemiology, and Risk Assessment. Toxicological Sciences 120, S130– S145 (2011).
7. Chatterjee, N. & Walker, G. C. Mechanisms of DNA damage, repair, and mutagenesis. Environmental and Molecular Mutagenesis 58, 235–263 (2017).
8. Cannan, W. J. & Pederson, D. S. Mechanisms and Consequences of Double-Strand DNA Break Formation in Chromatin. Journal of Cellular Physiology 231, 3–14 (2016).
9. LINDAHL, T. & BARNES, D. E. Repair of Endogenous DNA Damage. Cold Spring Harbor Symposia on Quantitative Biology 65, 127–134 (2000).
10. Lindahl, T. Instability and decay of the primary structure of DNA. Nature 362, 709–715 (1993). 11. Giglia-Mari, G., Zotter, A. & Vermeulen, W.
DNA Damage Response. Cold Spring Harbor Perspectives in Biology 3, a000745–a000745 (2011).
12. Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature
461, 1071–1078 (2009).
13. Lord, C. J. & Ashworth, A. The DNA damage
response and cancer therapy. Nature 481, 287– 294 (2012).
14. Ciccia, A. & Elledge, S. J. The DNA Damage Response: Making It Safe to Play with Knives. Molecular Cell 40, 179–204 (2010).
15. Currall, B. B., Chiangmai, C., Talkowski, M. E. & Morton, C. C. Mechanisms for Structural Variation in the Human Genome. Current Genetic Medicine Reports 1, 81–90 (2013).
16. Sogo, J. M. Fork Reversal and ssDNA Accumulation at Stalled Replication Forks Owing to Checkpoint Defects. Science 297, 599– 602 (2002).
17. Nyberg, K. A., Michelson, R. J., Putnam, C. W. & Weinert, T. A. Toward Maintaining the Genome: DNA Damage and Replication Checkpoints. Annual Review of Genetics 36, 617–656 (2002). 18. Marechal, A. & Zou, L. DNA Damage Sensing by
the ATM and ATR Kinases. Cold Spring Harbor Perspectives in Biology 5, a012716–a012716 (2013).
19. Abraham, R. T. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes & Development 15, 2177–2196 (2001).
20. Wallace, S. S. Base excision repair: A critical player in many games. DNA Repair 19, 14–26 (2014).
21. Marteijn, J. A., Lans, H., Vermeulen, W. & Hoeijmakers, J. H. J. Understanding nucleotide excision repair and its roles in cancer and ageing. Nature Reviews Molecular Cell Biology 15, 465–481 (2014).
22. Spivak, G. Nucleotide excision repair in humans. DNA Repair 36, 13–18 (2015).
23. Jiricny, J. The multifaceted mismatch-repair system. Nature Reviews Molecular Cell Biology 7, 335–346 (2006).
24. Edenberg, E. R., Downey, M. & Toczyski, D. Polymerase Stalling during Replication, Transcription and Translation. Current Biology
24, R445–R452 (2014).
25. Lambert, S. & Carr, A. M. Replication stress and genome rearrangements: lessons from yeast models. Current Opinion in Genetics & Development 23, 132–139 (2013).
BIB
cell death by apoptosis. Trends in MolecularMedicine 12, 440–450 (2006).
27. Gao, Y., Mutter-Rottmayer, E., Zlatanou, A., Vaziri, C. & Yang, Y. Mechanisms of Post-Replication DNA Repair. Genes 8, 64 (2017). 28. Yang, W. & Gao, Y. Translesion and Repair DNA
Polymerases: Diverse Structure and Mechanism. Annual Review of Biochemistry 87, 239–261 (2018).
29. Hoege, C., Pfander, B., Moldovan, G.-L., Pyrowolakis, G. & Jentsch, S. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419, 135–141 (2002). 30. Lovett, S. T. Template-switching during
replication fork repair in bacteria. DNA Repair 56, 118–128 (2017).
31. Lovett, S. T. Encoded errors: mutations and rearrangements mediated by misalignment at repetitive DNA sequences. Molecular Microbiology 52, 1243–1253 (2004).
32. Scully, R., Panday, A., Elango, R. & Willis, N. A. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nature Reviews Molecular Cell Biology 20, 698–714 (2019). 33. Chang, H. H. Y., Pannunzio, N. R., Adachi, N. &
Lieber, M. R. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nature Reviews Molecular Cell Biology 18, 495–506 (2017).
34. Sung, P. & Klein, H. Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nature Reviews Molecular Cell Biology 7, 739–750 (2006).
35. Aguilera, A. & Gómez-González, B. Genome instability: a mechanistic view of its causes and consequences. Nature Reviews Genetics 9, 204– 217 (2008).
36. Carvalho, C. M. B. & Lupski, J. R. Mechanisms underlying structural variant formation in genomic disorders. Nature Reviews Genetics 17, 224–238 (2016).
37. Shendure, J. & Akey, J. M. The origins, determinants, and consequences of human mutations. Science 349, 1478–1483 (2015). 38. Jeggo, P. A., Pearl, L. H. & Carr, A. M. DNA
repair, genome stability and cancer: a historical perspective. Nature Reviews Cancer 16, 35–42
(2016).
39. Negrini, S., Gorgoulis, V. G. & Halazonetis, T. D. Genomic instability — an evolving hallmark of cancer. Nature Reviews Molecular Cell Biology 11, 220–228 (2010).
40. Petr, M. A., Tulika, T., Carmona-Marin, L. M. & Scheibye-Knudsen, M. Protecting the Aging Genome. Trends in Cell Biology 30, 117–132 (2020). 41. Vijg, J. & Suh, Y. Genome Instability and Aging. Annual Review of Physiology 75, 645–668 (2013). 42. Aebersold, R. et al. How many human proteoforms are there? Nature Chemical Biology
14, 206–214 (2018).
43. Taverna, D. M. & Goldstein, R. A. Why are proteins marginally stable? Proteins: Structure, Function, and Genetics 46, 105–109 (2002). 44. Bloom, J. D., Raval, A. & Wilke, C. O.
Thermodynamics of Neutral Protein Evolution. Genetics 175, 255–266 (2007).
45. Chiti, F. & Dobson, C. M. Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. Annual Review of Biochemistry 86, 27–68 (2017). 46. Gsponer, J., Futschik, M. E., Teichmann, S. A. &
Babu, M. M. Tight Regulation of Unstructured Proteins: From Transcript Synthesis to Protein Degradation. Science 322, 1365–1368 (2008). 47. Uversky, V. N. Intrinsically Disordered Proteins
and Their “Mysterious” (Meta)Physics. Frontiers in Physics 7, (2019).
48. Tartaglia, G. G., Pechmann, S., Dobson, C. M. & Vendruscolo, M. Life on the edge: a link between gene expression levels and aggregation rates of human proteins. Trends in Biochemical Sciences
32, 204–206 (2007).
49. Hipp, M. S., Kasturi, P. & Hartl, F. U. The proteostasis network and its decline in ageing. Nature Reviews Molecular Cell Biology 20, 421– 435 (2019).
50. Joazeiro, C. A. P. Mechanisms and functions of ribosome-associated protein quality control. Nature Reviews Molecular Cell Biology 20, 368– 383 (2019).
51. Brandman, O. & Hegde, R. S. Ribosome-associated protein quality control. Nature Structural & Molecular Biology 23, 7–15 (2016). 52. Riba, A. et al. Protein synthesis rates and
ribosome occupancies reveal determinants of translation elongation rates. Proceedings of the National Academy of Sciences 116, 15023–15032 (2019).
53. Rodnina, M. v. The ribosome in action: Tuning of translational efficienc and protein folding. Protein Science 25, 1390–1406 (2016).
54. Holtkamp, W. et al. Cotranslational protein folding on the ribosome monitored in real time. Science 350, 1104–1107 (2015).
55. Stein, K. C. & Frydman, J. The stop-and-go traffi regulating protein biogenesis: How translation kinetics controls proteostasis. Journal of Biological Chemistry 294, 2076–2084 (2019). 56. Holtkamp, W. et al. Cotranslational protein
folding on the ribosome monitored in real time. Science 350, 1104–1107 (2015).
57. Waudby, C. A., Dobson, C. M. & Christodoulou, J. Nature and Regulation of Protein Folding on the Ribosome. Trends in Biochemical Sciences 44, 914–926 (2019).
58. Ivankov, D. N. & Finkelstein, A. v. Solution of Levinthal’s Paradox and a Physical Theory of Protein Folding Times. Biomolecules 10, 250 (2020).
59. Baldwin, R. L. The Search for Folding Intermediates and the Mechanism of Protein Folding. Annual Review of Biophysics 37, 1–21 (2008).
60. Finkelstein, A. v. 50+ Years of Protein Folding. Biochemistry (Moscow) 83, S3–S18 (2018). 61. Epstein, C. J., Goldberger, R. F. & Anfinsen,
C. B. The Genetic Control of Tertiary Protein Structure: Studies With Model Systems. Cold Spring Harbor Symposia on Quantitative Biology
28, (1963).
62. Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting Proteostasis for Disease Intervention. Science 319, 916–919 (2008). 63. Hartl, F. U., Bracher, A. & Hayer-Hartl, M.
Molecular chaperones in protein folding and proteostasis. Nature 475, 324–332 (2011). 64. Rosenzweig, R., Nillegoda, N. B., Mayer, M.
P. & Bukau, B. The Hsp70 chaperone network. Nature Reviews Molecular Cell Biology 20, 665– 680 (2019).
65. Kampinga, H. H. & Craig, E. A. The HSP70
chaperone machinery: J proteins as drivers of functional specifici y. Nature Reviews Molecular Cell Biology 11, 579–592 (2010).
66. Mayer, M. P. Intra-molecular pathways of allosteric control in Hsp70s. Philosophical Transactions of the Royal Society B: Biological Sciences 373, 20170183 (2018).
67. Morán Luengo, T., Mayer, M. P. & Rüdiger, S. G. D. The Hsp70–Hsp90 Chaperone Cascade in Protein Folding. Trends in Cell Biology 29, 164– 177 (2019).
68. Biebl, M. M. & Buchner, J. Structure, Function, and Regulation of the Hsp90 Machinery. Cold Spring Harbor Perspectives in Biology 11, a034017 (2019).
69. Basha, E., O’Neill, H. & Vierling, E. Small heat shock proteins and α-crystallins: dynamic proteins with flexible functions. Trends in Biochemical Sciences 37, 106–117 (2012).
70. Webster, J. M., Darling, A. L., Uversky, V. N. & Blair, L. J. Small Heat Shock Proteins, Big Impact on Protein Aggregation in Neurodegenerative Disease. Frontiers in Pharmacology 10, (2019). 71. Mogk, A., Ruger-Herreros, C. & Bukau, B.
Cellular Functions and Mechanisms of Action of Small Heat Shock Proteins. Annual Review of Microbiology 73, 89–110 (2019).
72. Żwirowski, S. et al. Hsp70 displaces small heat shock proteins from aggregates to initiate protein refolding. The EMBO Journal 36, 783– 796 (2017).
73. Kriegenburg, F., Ellgaard, L. & Hartmann-Petersen, R. Molecular chaperones in targeting misfolded proteins for ubiquitin-dependent degradation. FEBS Journal 279, 532–542 (2012). 74. Hansen, M., Rubinsztein, D. C. & Walker, D.
W. Autophagy as a promoter of longevity: insights from model organisms. Nature Reviews Molecular Cell Biology 19, 579–593 (2018). 75. Tokuriki, N. & Tawfik, D. S. Stability effects of
mutations and protein evolvability. Current Opinion in Structural Biology 19, 596–604 (2009). 76. Martin-Perez, M. & Villén, J. Determinants and Regulation of Protein Turnover in Yeast. Cell Systems 5, 283-294.e5 (2017).
77. Mathieson, T. et al. Systematic analysis of protein turnover in primary cells. Nature
BIB
Communications 9, 689 (2018).78. Amm, I., Sommer, T. & Wolf, D. H. Protein quality control and elimination of protein waste: The role of the ubiquitin–proteasome system. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1843, 182–196 (2014).
79. Braten, O. et al. Numerous proteins with unique characteristics are degraded by the 26S proteasome following monoubiquitination. Proceedings of the National Academy of Sciences
113, E4639–E4647 (2016).
80. Pohl, C. & Dikic, I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science 366, 818–822 (2019).
81. Vendruscolo, M., Knowles, T. P. J. & Dobson, C. M. Protein Solubility and Protein Homeostasis: A Generic View of Protein Misfolding Disorders. Cold Spring Harbor Perspectives in Biology 3, a010454–a010454 (2011).
82. Bento, C. F. et al. Mammalian Autophagy: How Does It Work? Annual Review of Biochemistry 85, 685–713 (2016).
83. Ihara, Y., Morishima-Kawashima, M. & Nixon, R. The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease. Cold Spring Harbor Perspectives in Medicine 2, a006361–a006361 (2012).
84. Ghosh, K. & Dill, K. Cellular Proteomes Have Broad Distributions of Protein Stability. Biophysical Journal 99, 3996–4002 (2010). 85. Tamás, M., Sharma, S., Ibstedt, S., Jacobson, T.
& Christen, P. Heavy Metals and Metalloids As a Cause for Protein Misfolding and Aggregation. Biomolecules 4, 252–267 (2014).
86. Lévy, E. et al. Causative Links between Protein Aggregation and Oxidative Stress: A Review. International Journal of Molecular Sciences 20, 3896 (2019).
87. Jackson, R. J., Hellen, C. U. T. & Pestova, T. v. The mechanism of eukaryotic translation initiation and principles of its regulation. Nature Reviews Molecular Cell Biology 11, 113–127 (2010). 88. Vihervaara, A., Duarte, F. M. & Lis, J. T. Molecular
mechanisms driving transcriptional stress responses. Nature Reviews Genetics 19, 385–397 (2018).
89. Costa-Mattioli, M. & Walter, P. The integrated
stress response: From mechanism to disease. Science 368, (2020).
90. Fusakio, M. E. et al. Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver. Molecular Biology of the Cell 27, 1536–1551 (2016). 91. Shpilka, T. & Haynes, C. M. The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nature Reviews Molecular Cell Biology 19, 109–120 (2018).
92. Higuchi-Sanabria, R., Frankino, P. A., Paul, J. W., Tronnes, S. U. & Dillin, A. A Futile Battle? Protein Quality Control and the Stress of Aging. Developmental Cell 44, 139–163 (2018).
93. Richter, K., Haslbeck, M. & Buchner, J. The Heat Shock Response: Life on the Verge of Death. Molecular Cell 40, 253–266 (2010).
94. Karagöz, G. E., Acosta-Alvear, D. & Walter, P. The Unfolded Protein Response: Detecting and Responding to Fluctuations in the Protein-Folding Capacity of the Endoplasmic Reticulum. Cold Spring Harbor Perspectives in Biology 11, a033886 (2019).
95. Klaips, C. L., Jayaraj, G. G. & Hartl, F. U. Pathways of cellular proteostasis in aging and disease. Journal of Cell Biology 217, 51–63 (2018).
96. Kampinga, H. H. & Bergink, S. Heat shock proteins as potential targets for protective strategies in neurodegeneration. The Lancet Neurology 15, 748–759 (2016).
97. Jackson, M. & Hewitt, E. Why are Functional Amyloids Non-Toxic in Humans? Biomolecules 7, (2017).
98. Gidalevitz, T., Kikis, E. A. & Morimoto, R. I. A cellular perspective on conformational disease: the role of genetic background and proteostasis networks. Current Opinion in Structural Biology
20, 23–32 (2010).
99. Bondarev, S., Antonets, K., Kajava, A., Nizhnikov, A. & Zhouravleva, G. Protein Co-Aggregation Related to Amyloids: Methods of Investigation, Diversity, and Classification. International Journal of Molecular Sciences 19, 2292 (2018). 100. Santra, M., Dill, K. A. & de Graff, A. M. R.
Proteostasis collapse is a driver of cell aging and death. Proceedings of the National Academy of
Sciences 116, 22173–22178 (2019).
101. Labbadia, J. & Morimoto, R. I. The Biology of Proteostasis in Aging and Disease. Annual Review of Biochemistry 84, 435–464 (2015). 102. Sandri, M., Coletto, L., Grumati, P. & Bonaldo,
P. Misregulation of autophagy and protein degradation systems in myopathies and muscular dystrophies. Journal of Cell Science 126, 5325–5333 (2013).
103. Henning, R. H. & Brundel, B. J. J. M. Proteostasis in cardiac health and disease. Nature Reviews Cardiology 14, 637–653 (2017).
104. Jaisson, S. & Gillery, P. Impaired proteostasis: role in the pathogenesis of diabetes mellitus. Diabetologia 57, 1517–1527 (2014).
105. McGrail, D. J. et al. Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer. Cancer Cell 37, 371-386.e12 (2020).
106. Dai, C., Dai, S. & Cao, J. Proteotoxic stress of cancer: Implication of the heat-shock response in oncogenesis. Journal of Cellular Physiology
227, 2982–2987 (2012).
107. Deshaies, R. J. Proteotoxic crisis, the ubiquitin-proteasome system, and cancer therapy. BMC Biology 12, 94 (2014).
108. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The Hallmarks of Aging. Cell 153, 1194–1217 (2013).
109. Kaushik, S. & Cuervo, A. M. Proteostasis and aging. Nature Medicine 21, 1406–1415 (2015). 110. Priestley, P. et al. Pan-cancer whole-genome
analyses of metastatic solid tumours. Nature
575, 210–216 (2019).
111. Vogelstein, B. et al. Cancer Genome Landscapes. Science 339, 1546–1558 (2013).
112. Pan-cancer analysis of whole genomes. Nature
578, 82–93 (2020).
113. Hou, Y., Song, H., Croteau, D. L., Akbari, M. & Bohr, V. A. Genome instability in Alzheimer disease. Mechanisms of Ageing and Development
161, 83–94 (2017).
114. Sepe, S. et al. Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson’s Disease. Cell Reports 15, 1866–1875 (2016).
115. Hamczyk, M. R. et al. Progerin accelerates atherosclerosis by inducing endoplasmic
reticulum stress in vascular smooth muscle cells. EMBO Molecular Medicine 11, (2019).
116. Zhu, P. J. et al. Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome. Science 366, 843–849 (2019).
117. Chatzidoukaki, O., Goulielmaki, E., Schumacher, B. & Garinis, G. A. DNA Damage Response and Metabolic Reprogramming in Health and Disease. Trends in Genetics (2020) doi:10.1016/j. tig.2020.06.018.
118. Xie, J. L. & Jarosz, D. F. Mutations, protein homeostasis, and epigenetic control of genome integrity. DNA Repair 71, 23–32 (2018).
119. Farmer, K. M. et al. P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s disease. Acta Neuropathologica Communications 8, 132 (2020).
120. Illuzzi, J., Yerkes, S., Parekh-Olmedo, H. & Kmiec, E. B. DNA breakage and induction of DNA damage response proteins precede the appearance of visible mutant huntingtin aggregates. Journal of Neuroscience Research 87, 733–747 (2009).
121. Vasquez, V. et al. Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease. Journal of Alzheimer’s Disease 60, S133– S150 (2017).
122. Lévy, E. et al. Causative Links between Protein Aggregation and Oxidative Stress: A Review. International Journal of Molecular Sciences 20, 3896 (2019).
123. Ludtmann, M. H. R. et al. α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease. Nature Communications 9, 2293 (2018). 124. Vehvilainen, P., Koistinaho, J. & Gundars,
G. Mechanisms of mutant SOD1 induced mitochondrial toxicity in amyotrophic lateral sclerosis. Frontiers in Cellular Neuroscience 8, (2014).
125. Wang, P. et al. TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. PLOS Genetics 15, e1007947 (2019).
BIB
huntingtin and mitochondrial dysfunction.Trends in Neurosciences 31, 609–616 (2008). 127. Moreira, P. I., Carvalho, C., Zhu, X., Smith, M.
A. & Perry, G. Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1802, 2–10 (2010).
128. Enokido, Y. et al. Mutant huntingtin impairs Ku70-mediated DNA repair. Journal of Cell Biology 189, 425–443 (2010).
129. Gao, R. et al. Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription. eLife 8, (2019).
130. Nakamura, M., Kaneko, S., Dickson, D. W. & Kusaka, H. Aberrant Accumulation of BRCA1 in Alzheimer Disease and Other Tauopathies. Journal of Neuropathology & Experimental Neurology (2019) doi:10.1093/jnen/nlz107. 131. Suberbielle, E. et al. DNA repair factor BRCA1
depletion occurs in Alzheimer brains and impairs cognitive function in mice. Nature Communications 6, 8897 (2015).
132. Bordoni, M. et al. Nuclear Phospho-SOD1 Protects DNA from Oxidative Stress Damage in Amyotrophic Lateral Sclerosis. Journal of Clinical Medicine 8, 729 (2019).
133. Bukar Maina, M., Al-Hilaly, Y. & Serpell, L. Nuclear Tau and Its Potential Role in Alzheimer’s Disease. Biomolecules 6, 9 (2016).
134. Schaser, A. J. et al. Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders. Scientific Reports 9, 10919 (2019).
135. Wang, H. et al. Mutant FUS causes DNA ligation defects to inhibit oxidative damage repair in Amyotrophic Lateral Sclerosis. Nature Communications 9, 3683 (2018).
136. ben Yehuda, A. et al. Ubiquitin Accumulation on Disease Associated Protein Aggregates Is Correlated with Nuclear Ubiquitin Depletion, Histone De-Ubiquitination and Impaired DNA Damage Response. PLOS ONE 12, e0169054 (2017).
137. Knighton, L. E. & Truman, A. W. Role of the Molecular Chaperones Hsp70 and Hsp90 in the DNA Damage Response. in 345–358 (2019). doi:10.1007/978-3-030-03952-3_18.
138. Sottile, M. L. & Nadin, S. B. Heat shock proteins and DNA repair mechanisms: an updated overview. Cell Stress and Chaperones 23, 303–315 (2018).
139. Dubrez, L., Causse, S., Borges Bonan, N., Dumétier, B. & Garrido, C. Heat-shock proteins: chaperoning DNA repair. Oncogene 39, 516–529 (2020).
140. Oda, T., Hayano, T., Miyaso, H., Takahashi, N. & Yamashita, T. Hsp90 regulates the Fanconi anemia DNA damage response pathway. Blood
109, 5016–5026 (2007).
141. Quanz, M. et al. Heat Shock Protein 90α (Hsp90α) Is Phosphorylated in Response to DNA Damage and Accumulates in Repair Foci. Journal of Biological Chemistry 287, 8803–8815 (2012).
142. Sekimoto, T. et al. The Molecular Chaperone Hsp90 Regulates Accumulation of DNA Polymerase η at Replication Stalling Sites in UV-Irradiated Cells. Molecular Cell 37, 79–89 (2010). 143. Dote, H., Burgan, W. E., Camphausen, K. &
Tofilon, P. J. Inhibition of Hsp90 Compromises the DNA Damage Response to Radiation. Cancer Research 66, 9211–9220 (2006).
144. Ko, J.-C. et al. HSP90 inhibition induces cytotoxicity via down-regulation of Rad51 expression and DNA repair capacity in non-small cell lung cancer cells. Regulatory Toxicology and Pharmacology 64, 415–424 (2012).
145. Solier, S. et al. Heat shock protein 90 (HSP90 ), a substrate and chaperone of DNA-PK necessary for the apoptotic response. Proceedings of the National Academy of Sciences 109, 12866–12872 (2012).
146. Fang, Q. et al. HSP90 regulates DNA repair via the interaction between XRCC1 and DNA polymerase β. Nature Communications 5, 5513 (2014).
147. Cheng, A. N. et al. Cdc7-Dbf4-mediated phosphorylation of HSP90-S164 stabilizes HSP90-HCLK2-MRN complex to enhance ATR/ ATM signaling that overcomes replication stress in cancer. Scientific Reports 7, 17024 (2017). 148. Echtenkamp, F. J. et al. Global Functional Map
of the p23 Molecular Chaperone Reveals an Extensive Cellular Network. Molecular Cell 43,
229–241 (2011).
149. Pickles, S., Vigié, P. & Youle, R. J. Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance. Current Biology 28, R170–R185 (2018).
150. Ravanelli, S., den Brave, F. & Hoppe, T. Mitochondrial Quality Control Governed by Ubiquitin. Frontiers in Cell and Developmental Biology 8, (2020).
151. Brinkmann, K., Schell, M., Hoppe, T. & Kashkar, H. Regulation of the DNA damage response by ubiquitin conjugation. Frontiers in Genetics 6, (2015).
152. Guo, C. & Zhao, Y. Autophagy and DNA damage repair. Genome Instability & Disease (2020) doi:10.1007/s42764-020-00016-9.
153. Hewitt, G. et al. SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair. Autophagy 12, 1917–1930 (2016).
154. Hewitt, G. & Korolchuk, V. I. Repair, Reuse, Recycle: The Expanding Role of Autophagy in Genome Maintenance. Trends in Cell Biology 27, 340–351 (2017).
155. Bergink, S. & Jentsch, S. Principles of ubiquitin and SUMO modifications in DNA repair. Nature
458, 461–467 (2009).
156. Arlow, T., Scott, K., Wagenseller, A. & Gammie, A. Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2. Proceedings of the National Academy of Sciences 110, 246–251 (2013). 157. Karpov, D. S., Spasskaya, D. S., Tutyaeva, V.
v., Mironov, A. S. & Karpov, V. L. Proteasome inhibition enhances resistance to DNA damage via upregulation of Rpn4-dependent DNA repair genes. FEBS Letters 587, 3108–3114 (2013). 158. Sciascia, N. et al. Suppressing proteasome
mediated processing of topoisomerase II DNA-protein complexes preserves genome integrity. eLife 9, (2020).
159. Monaco, A. & Fraldi, A. Protein Aggregation and Dysfunction of Autophagy-Lysosomal Pathway: A Vicious Cycle in Lysosomal Storage Diseases. Frontiers in Molecular Neuroscience 13, (2020). 160. Thibaudeau, T. A., Anderson, R. T. & Smith,
D. M. A common mechanism of proteasome impairment by neurodegenerative
disease-associated oligomers. Nature Communications 9, 1097 (2018).
161. Chen, G., Bradford, W. D., Seidel, C. W. & Li, R. Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy. Nature 482, 246–250 (2012).
162. Kaya, A. et al. Molecular signatures of aneuploidy-driven adaptive evolution. Nature Communications 11, 588 (2020).
163. Rancati, G. et al. Aneuploidy Underlies Rapid Adaptive Evolution of Yeast Cells Deprived of a Conserved Cytokinesis Motor. Cell 135, 879–893 (2008).
164. Brown, J. S. & Jackson, S. P. Ubiquitylation, neddylation and the DNA damage response. Open Biology 5, 150018 (2015).
165. Wang, Z., Zhu, W.-G. & Xu, X. Ubiquitin-like modifications in the DNA damage response. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 803–805, 56–75 (2017).
166. Liebelt, F. & Vertegaal, A. C. O. Ubiquitin-dependent and inUbiquitin-dependent roles of SUMO in proteostasis. American Journal of Physiology-Cell Physiology 311, C284–C296 (2016).
167. Park, C.-W. & Ryu, K.-Y. Cellular ubiquitin pool dynamics and homeostasis. BMB Reports 47, 475–482 (2014).
168. Dantuma, N. P., Groothuis, T. A. M., Salomons, F. A. & Neefjes, J. A dynamic ubiquitin equilibrium couples proteasomal activity to chromatin remodeling. Journal of Cell Biology 173, 19–26 (2006).
169. Farrawell, N. E. et al. SOD1-A4V aggregation alters ubiquitin homeostasis in a cell model of ALS. Journal of Cell Science 131, jcs209122 (2018). 170. Mimnaugh, E. G., Chen, H. Y., Davie, J. R., Celis,
J. E. & Neckers, L. Rapid Deubiquitination of Nucleosomal Histones in Human Tumor Cells Caused by Proteasome Inhibitors and Stress Response Inducers: Effects on Replication, Transcription, Translation, and the Cellular Stress Response †. Biochemistry 36, 14418–14429
(1997).
171. Bence, N. F. Impairment of the Ubiquitin-Proteasome System by Protein Aggregation. Science 292, 1552–1555 (2001).
BIB
172. Enchev, R. I., Schulman, B. A. & Peter, M. Proteinneddylation: beyond cullin–RING ligases. Nature Reviews Molecular Cell Biology 16, 30–44 (2015). 173. van Ham, T. J., Breitling, R., Swertz, M. A. &
Nollen, E. A. A. Neurodegenerative diseases: Lessons from genome-wide screens in small model organisms. EMBO Molecular Medicine 1, 360–370 (2009).
174. McKinnon, P. J. ATM and the Molecular Pathogenesis of Ataxia Telangiectasia. Annual Review of Pathology: Mechanisms of Disease 7, 303–321 (2012).
175. Barzilai, A., Rotman, G. & Shilow, Y. ATM deficiencyand oxidative stress: a new dimension of defective response to DNA damage. DNA Repair 1, 3–25 (2002).
176. Liu, N. et al. ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes. Laboratory Investigation 85, 1471– 1480 (2005).
177. Yan, M. et al. Endoplasmic Reticulum Stress and Unfolded Protein Response in Atm-Deficient Thymocytes and Thymic Lymphoma Cells Are Attributable to Oxidative Stress. Neoplasia 10, 160–167 (2008).
178. Guo, Z., Kozlov, S., Lavin, M. F., Person, M. D. & Paull, T. T. ATM Activation by Oxidative Stress. Science 330, 517–521 (2010).
179. Corcoles-Saez, I. et al. Essential Function of Mec1, the Budding Yeast ATM/ATR Checkpoint-Response Kinase, in Protein Homeostasis. Developmental Cell 46, 495-503.e2 (2018). 180. Shiloh, Y. The cerebellar degeneration in
ataxia-telangiectasia: A case for genome instability. DNA Repair 95, 102950 (2020).
181. Croteau, D. L., Popuri, V., Opresko, P. L. & Bohr, V. A. Human RecQ Helicases in DNA Repair, Recombination, and Replication. Annual Review of Biochemistry 83, 519–552 (2014).
182. Talaei, F., van Praag, V. M. & Henning, R. H. Hydrogen sulfide restores a normal morphological phenotype in Werner syndrome fibroblasts, attenuates oxidative damage and modulates mTOR pathway. Pharmacological Research 74, 34–44 (2013).
183. Vessoni, A. T., Guerra, C. C. C., Kajitani, G. S., Nascimento, L. L. S. & Garcia, C. C. M. Cockayne
Syndrome: The many challenges and approaches to understand a multifaceted disease. Genetics and Molecular Biology 43, (2020).
184. Alupei, M. C. et al. Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome. Cell Reports 23, 1612–1619 (2018).
185. Kraemer, K. H. Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Archives of Dermatology
123, 241–250 (1987).
186. Arczewska, K. D. et al. Active transcriptomic and proteomic reprogramming in the C. elegans nucleotide excision repair mutant xpa-1. Nucleic Acids Research 41, 5368–5381 (2013).
187. de Sousa Leal, A. M. et al. XPA deficiency affects the ubiquitin-proteasome system function. DNA Repair 94, 102937 (2020).
188. Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016).
189. Brazhnik, K. et al. Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver. Science Advances 6, eaax2659 (2020). 190. Laurie, C. C. et al. Detectable clonal mosaicism
from birth to old age and its relationship to cancer. Nature Genetics 44, 642–650 (2012). 191. Lodato, M. A. et al. Aging and neurodegeneration
are associated with increased mutations in single human neurons. Science 359, 555–559 (2018).
192. Martincorena, I. et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).
193. Zhang, L. et al. Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan. Proceedings of the National Academy of Sciences 116, 9014–9019 (2019). 194. Redler, R. L., Das, J., Diaz, J. R. & Dokholyan, N.
v. Protein Destabilization as a Common Factor in Diverse Inherited Disorders. Journal of Molecular Evolution 82, 11–16 (2016).
195. Matsui, D., Nakano, S., Dadashipour, M. & Asano, Y. Rational identification of aggregation hotspots based on secondary structure and
amino acid hydrophobicity. Scientific Reports 7, 9558 (2017).
196. Dettmer, U. et al. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nature Communications 6, 7314 (2015).
197. Boopathy, S. et al. Structural basis for mutation-induced destabilization of profilin 1 in ALS. Proceedings of the National Academy of Sciences
112, 7984–7989 (2015).
198. Wilcken, R., Wang, G., Boeckler, F. M. & Fersht, A. R. Kinetic mechanism of p53 oncogenic mutant aggregation and its inhibition. Proceedings of the National Academy of Sciences 109, 13584– 13589 (2012).
199. Booth, D. R. et al. Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature 385, 787–793 (1997).
200. Lim, K. H. et al. Pathogenic Mutations Induce Partial Structural Changes in the Native β-Sheet Structure of Transthyretin and Accelerate Aggregation. Biochemistry 56, 4808–4818 (2017).
201. de Baets, G., van Doorn, L., Rousseau, F. & Schymkowitz, J. Increased Aggregation Is More Frequently Associated to Human Disease-Associated Mutations Than to Neutral Polymorphisms. PLOS Computational Biology 11, e1004374 (2015).
202. Spillantini, M. G. & Goedert, M. Tau pathology and neurodegeneration. The Lancet Neurology
12, 609–622 (2013).
203. Solomon, J. P., Page, L. J., Balch, W. E. & Kelly, J. W. Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention. Critical Reviews in Biochemistry and Molecular Biology 47, 282–296 (2012).
204. Chen, G. et al. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacologica Sinica 38, 1205–1235 (2017). 205. Raimondi, S. et al. Effects of the Known
Pathogenic Mutations on the Aggregation Pathway of the Amyloidogenic Peptide of Apolipoprotein A-I. Journal of Molecular Biology
407, 465–476 (2011).
206. Benson, M. D. et al. A New Human Hereditary Amyloidosis: The Result of a Stop-Codon Mutation in the Apolipoprotein AII Gene. Genomics 72, 272–277 (2001).
207. Bernardi, L. & Bruni, A. C. Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-Terminal vs. N-Terminal Domain, a Review. International Journal of Molecular Sciences 20, 3606 (2019).
208. Niblock, M. & Gallo, J.-M. Tau alternative splicing in familial and sporadic tauopathies. Biochemical Society Transactions 40, 677–680 (2012).
209. Sauna, Z. E. & Kimchi-Sarfaty, C. Understanding the contribution of synonymous mutations to human disease. Nature Reviews Genetics 12, 683–691 (2011).
210. Walsh, I. M., Bowman, M. A., Soto Santarriaga, I. F., Rodriguez, A. & Clark, P. L. Synonymous codon substitutions perturb cotranslational protein folding in vivo and impair cell fitness. Proceedings of the National Academy of Sciences
117, 3528–3534 (2020).
211. Russo, C. et al. Protein aggregation of the p63 transcription factor underlies severe skin fragility in AEC syndrome. Proceedings of the National Academy of Sciences 115, E906–E915 (2018).
212. Palumbo, E., Zhao, B., Xue, B., Uversky, V. N. & Davé, V. Analyzing aggregation propensities of clinically relevant PTEN mutants: a new culprit in pathogenesis of cancer and other PTENopathies. Journal of Biomolecular Structure and Dynamics 38, 2253–2266 (2020).
213. Shigemizu, D. et al. A practical method to detect SNVs and indels from whole genome and exome sequencing data. Scientific Reports 3, 2161 (2013). 214. Baker, M. Structural variation: the genome’s
hidden architecture. Nature Methods 9, 133–137 (2012).
215. Abel, H. J. et al. Mapping and characterization of structural variation in 17,795 human genomes. Nature 583, 83–89 (2020).
216. Forsberg, L. A. et al. Age-Related Somatic Structural Changes in the Nuclear Genome of Human Blood Cells. The American Journal of Human Genetics 90, 217–228 (2012).
BIB
217. Weischenfeldt, J., Symmons, O., Spitz, F. &Korbel, J. O. Phenotypic impact of genomic structural variation: insights from and for human disease. Nature Reviews Genetics 14, 125– 138 (2013).
218. Yi, K. & Ju, Y. S. Patterns and mechanisms of structural variations in human cancer. Experimental & Molecular Medicine 50, 98 (2018). 219. Potter, H. et al. Chromosome Instability and
Mosaic Aneuploidy in Neurodegenerative and Neurodevelopmental Disorders. Frontiers in Genetics 10, (2019).
220. Shepherd, C. E., Yang, Y. & Halliday, G. M. Region- and Cell-specific Aneuploidy in Brain Aging and Neurodegeneration. Neuroscience 374, 326–334 (2018).
221. Perez-Rodriguez, D. et al. Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing. Acta Neuropathologica Communications 7, 219 (2019).
222. Rovelet-Lecrux, A. et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nature Genetics 38, 24–26 (2006). 223. Lott, I. T. & Head, E. Dementia in Down
syndrome: unique insights for Alzheimer disease research. Nature Reviews Neurology 15, 135–147 (2019).
224. Oromendia, A. B., Dodgson, S. E. & Amon, A. Aneuploidy causes proteotoxic stress in yeast. Genes & Development 26, 2696–2708 (2012). 225. Sunshine, A. B. et al. Aneuploidy shortens
replicative lifespan in Saccharomyces cerevisiae. Aging Cell 15, 317–324 (2016).
226. Brennan, C. M. et al. Protein aggregation mediates stoichiometry of protein complexes in aneuploid cells. Genes & Development 33, 1031– 1047 (2019).
227. Stingele, S. et al. Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells. Molecular Systems Biology 8, 608 (2012).
228. Oromendia, A. B. & Amon, A. Aneuploidy: implications for protein homeostasis and disease. Disease Models & Mechanisms 7, 15–20 (2014).
229. Bos, H. van den, Spierings, D. C. J., Foijer, F. & Lansdorp, P. M. Does Aneuploidy in the Brain Play a Role in Neurodegenerative Disease? in Chromosomal Abnormalities - A Hallmark Manifestation of Genomic Instability (2017). doi:10.5772/67886.
230. Revay, T., Oluwole, O., Kroetsch, T. & King, W. A. In vivo and in vitro ageing results in accumulation of de novo copy number variations in bulls. Scientific Reports 7, 1631 (2017).
231. Villela, D. et al. Increased DNA Copy Number Variation Mosaicism in Elderly Human Brain. Neural Plasticity 2018, 1–9 (2018).
232. Spielmann, M., Lupiáñez, D. G. & Mundlos, S. Structural variation in the 3D genome. Nature Reviews Genetics 19, 453–467 (2018).
233. Paulson, H. Repeat expansion diseases. in 105–123 (2018). doi:10.1016/B978-0-444-63233-3.00009-9.
234. Gidalevitz, T. Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases. Science 311, 1471–1474 (2006). 235. Adegbuyiro, A., Sedighi, F., Pilkington, A.
W., Groover, S. & Legleiter, J. Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease. Biochemistry 56, 1199–1217 (2017).
236. Kuiper, E. F. E., de Mattos, E. P., Jardim, L. B., Kampinga, H. H. & Bergink, S. Chaperones in Polyglutamine Aggregation: Beyond the Q-Stretch. Frontiers in Neuroscience 11, (2017). 237. Pirone, L. et al. Molecular insights into the
role of the polyalanine region in mediating <scp>PHOX</scp> 2B aggregation. The FEBS Journal 286, 2505–2521 (2019).
238. Polling, S. et al. Polyalanine expansions drive a shift into α-helical clusters without amyloid-fibril formation. Nature Structural & Molecular Biology 22, 1008–1015 (2015).
239. Ellerby, L. M. Repeat Expansion Disorders: Mechanisms and Therapeutics. Neurotherapeutics 16, 924–927 (2019).
240. Banez-Coronel, M. & Ranum, L. P. W. Repeat-associated non-AUG (RAN) translation: insights from pathology. Laboratory Investigation 99, 929–942 (2019).
Repeat-associated non-ATG (RAN) translation. Journal of Biological Chemistry 293, 16127–16141 (2018).
242. Swinnen, B., Robberecht, W. & van den Bosch, L. RNA toxicity in non-coding repeat expansion disorders. The EMBO Journal 39, (2020). 243. Gudde, A. E. E. G. et al. Antisense transcription
of the myotonic dystrophy locus yields low-abundant RNAs with and without (CAG)n repeat. RNA Biology 14, 1374–1388 (2017). 244. Zu, T. et al. Non-ATG–initiated translation
directed by microsatellite expansions. Proceedings of the National Academy of Sciences
108, 260–265 (2011).
245. Balendra, R. & Isaacs, A. M. C9orf72-mediated ALS and FTD: multiple pathways to disease. Nature Reviews Neurology 14, 544–558 (2018). 246. Zu, T. et al. RAN proteins and RNA foci from
antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proceedings of the National Academy of Sciences 110, E4968–E4977 (2013).
247. Green, K. M. et al. RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. Nature Communications 8, 2005 (2017).
248. Cortese, A. et al. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nature Genetics 51, 649–658 (2019).
249. Ishiura, H. et al. Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nature Genetics 51, 1222– 1232 (2019).
250. López Castel, A., Cleary, J. D. & Pearson, C. E. Repeat instability as the basis for human diseases and as a potential target for therapy. Nature Reviews Molecular Cell Biology 11, 165–170 (2010).
251. Nordin, A. et al. Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD. Human Molecular Genetics 24, 3133–3142 (2015).
252. Cancel, G. et al. Somatic mosaicism of the CAG repeat expansion in spinocerebellar ataxia type
3/Machado-Joseph disease. Human Mutation 11, 23–27 (1998).
253. Kennedy, L. Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Human Molecular Genetics 12, 3359–3367 (2003). 254. Ciosi, M. et al. A genetic association study of
glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes. EBioMedicine 48, 568–580 (2019). 255. Morales, F. et al. Somatic instability of the
expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity. Human Molecular Genetics 21, 3558–3567 (2012). 256. Swami, M. et al. Somatic expansion of the
Huntington’s disease CAG repeat in the brain is associated with an earlier age of disease onset. Human Molecular Genetics 18, 3039–3047 (2009). 257. Sanchez-Contreras, M. & Cardozo-Pelaez, F.
Age-related length variability of polymorphic CAG repeats. DNA Repair 49, 26–32 (2017). 258. Lans, H., Hoeijmakers, J. H. J., Vermeulen, W.
& Marteijn, J. A. The DNA damage response to transcription stress. Nature Reviews Molecular Cell Biology 20, 766–784 (2019).
259. Ou, H.-L. & Schumacher, B. DNA damage responses and p53 in the aging process. Blood
131, 488–495 (2018).
260. Brégeon, D. & Doetsch, P. W. Transcriptional mutagenesis: causes and involvement in tumour development. Nature Reviews Cancer 11, 218–227 (2011).
261. Brégeon, D., Doddridge, Z. A., You, H. J., Weiss, B. & Doetsch, P. W. Transcriptional Mutagenesis Induced by Uracil and 8-Oxoguanine in Escherichia coli. Molecular Cell 12, 959–970 (2003).
262. Basu, S., Je, G. & Kim, Y.-S. Transcriptional mutagenesis by 8-oxodG in α-synuclein aggregation and the pathogenesis of Parkinson’s disease. Experimental & Molecular Medicine 47, e179–e179 (2015).
263. Clementi, E. et al. Persistent DNA damage triggers activation of the integrated stress response to promote cell survival under nutrient
BIB
restriction. BMC Biology 18, 36 (2020).264. Cordaux, R. & Batzer, M. A. The impact of retrotransposons on human genome evolution. Nature Reviews Genetics 10, 691–703 (2009). 265. Muotri, A. R. et al. Somatic mosaicism in
neuronal precursor cells mediated by L1 retrotransposition. Nature 435, 903–910 (2005). 266. Upton, K. R. et al. Ubiquitous L1 Mosaicism in
Hippocampal Neurons. Cell 161, 228–239 (2015). 267. Li, W. et al. Human endogenous retrovirus-K
contributes to motor neuron disease. Science Translational Medicine 7, 307ra153-307ra153 (2015).
268. Jönsson, M. E., Garza, R., Johansson, P. A. & Jakobsson, J. Transposable Elements: A Common Feature of Neurodevelopmental and Neurodegenerative Disorders. Trends in Genetics 36, 610–623 (2020).
269. Yu, M. & Ren, B. The Three-Dimensional Organization of Mammalian Genomes. Annual Review of Cell and Developmental Biology 33, 265–289 (2017).
270. Evans, S. A., Horrell, J. & Neretti, N. The three-dimensional organization of the genome in cellular senescence and age-associated diseases. Seminars in Cell & Developmental Biology 90, 154–160 (2019).
271. Prohaska, A. et al. Human Disease Variation in the Light of Population Genomics. Cell 177, 115– 131 (2019).
272. Gidalevitz, T., Wang, N., Deravaj, T., Alexander-Floyd, J. & Morimoto, R. I. Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegans model for polyglutamine disease. BMC Biology 11, 100 (2013).
273. Gidalevitz, T., Prahlad, V. & Morimoto, R. I. The Stress of Protein Misfolding: From Single Cells to Multicellular Organisms. Cold Spring Harbor Perspectives in Biology 3, a009704–a009704 (2011).
274. Gidalevitz, T., Krupinski, T., Garcia, S. & Morimoto, R. I. Destabilizing Protein Polymorphisms in the Genetic Background Direct Phenotypic Expression of Mutant SOD1 Toxicity. PLoS Genetics 5, e1000399 (2009). 275. Ciryam, P. et al. A transcriptional signature
of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation. Proceedings of the National Academy of Sciences
113, 4753–4758 (2016).
276. Goldschmidt, L., Teng, P. K., Riek, R. & Eisenberg, D. Identifying the amylome, proteins capable of forming amyloid-like fibrils. Proceedings of the National Academy of Sciences 107, 3487–3492 (2010).
277. Fares, M. A., Ruiz-González, M. X., Moya, A., Elena, S. F. & Barrio, E. GroEL buffers against deleterious mutations. Nature 417, 398–398 (2002).
278. Maisnier-Patin, S. et al. Genomic buffering mitigates the effects of deleterious mutations in bacteria. Nature Genetics 37, 1376–1379 (2005). 279. Gragerov, A. et al. Cooperation of GroEL/ GroES and DnaK/DnaJ heat shock proteins in preventing protein misfolding in Escherichia coli. Proceedings of the National Academy of Sciences 89, 10341–10344 (1992).
280. Jarosz, D. F., Taipale, M. & Lindquist, S. Protein Homeostasis and the Phenotypic Manifestation of Genetic Diversity: Principles and Mechanisms. Annual Review of Genetics 44, 189–216 (2010). 281. Zhao, L. et al. The Hsp70 Chaperone System
Stabilizes a Thermo-sensitive Subproteome in E. coli. Cell Reports 28, 1335-1345.e6 (2019). 282. Calderwood, S. K. & Gong, J. Heat Shock
Proteins Promote Cancer: It’s a Protection Racket. Trends in Biochemical Sciences 41, 311– 323 (2016).
283. Borkovich, K. A., Farrelly, F. W., Finkelstein, D. B., Taulien, J. & Lindquist, S. hsp82 is an essential protein that is required in higher concentrations for growth of cells at higher temperatures. Molecular and Cellular Biology 9, 3919–3930 (1989).
284. Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nature Reviews Cancer 5, 761–772 (2005).
285. Nagata, Y. et al. The stabilization mechanism of mutant-type p53 by impaired ubiquitination: the loss of wild-type p53 function and the hsp90 association. Oncogene 18, 6037–6049 (1999). 286. Boysen, M., Kityk, R. & Mayer, M. P. Hsp70-
Conformation of p53 DNA Binding Domain and p53 Cancer Variants. Molecular Cell 74, 831-843. e4 (2019).
287. Karras, G. I. et al. HSP90 Shapes the Consequences of Human Genetic Variation. Cell
168, 856-866.e12 (2017).
288. Donnelly, N., Passerini, V., Dürrbaum, M., Stingele, S. & Storchová, Z. HSF1 deficiency and impaired HSP90-dependent protein folding are hallmarks of aneuploid human cells. The EMBO Journal 33, 2374–2387 (2014).
289. Antonarakis, S. E. et al. Down syndrome. Nature Reviews Disease Primers 6, 9 (2020).
290. Gonzalo, S. & Kreienkamp, R. DNA repair defects and genome instability in Hutchinson– Gilford Progeria Syndrome. Current Opinion in Cell Biology 34, 75–83 (2015).
291. Musich, P. R. & Zou, Y. Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A. Aging 1, 28– 37 (2009).
292. Aivazidis, S. et al. The burden of trisomy 21 disrupts the proteostasis network in Down syndrome. PLOS ONE 12, e0176307 (2017). 293. Lanzillotta, C. et al. Early and Selective
Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models. Journal of Alzheimer’s Disease
62, 347–359 (2018).
294. Paradisi, M. et al. Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stress. BMC Cell Biology 6, 27 (2005).
295. Hirata, K. et al. 4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates. Scientific Reports 10, 14047 (2020).
296. Nawa, N. et al. Elimination of protein aggregates prevents premature senescence in human trisomy 21 fibrobl sts. PLOS ONE 14, e0219592 (2019).
297. Jeppesen, D. K., Bohr, V. A. & Stevnsner, T. DNA repair deficiency in neurodegeneration. Progress in Neurobiology 94, 166–200 (2011). 298. Martincorena, I. & Campbell, P. J. Somatic
mutation in cancer and normal cells. Science 349,
1483–1489 (2015).
299. Park, J. S. et al. Brain somatic mutations observed in Alzheimer’s disease associated with aging and dysregulation of tau phosphorylation. Nature Communications 10, 3090 (2019). 300. Vijg, J. & Dong, X. Pathogenic Mechanisms of
Somatic Mutation and Genome Mosaicism in Aging. Cell 182, 12–23 (2020).
301. Georgiadis, M. M. et al. Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons. DNA Repair 41, 32–41 (2016). 302. Gioia, U. et al. Pharmacological boost of DNA
damage response and repair by enhanced biogenesis of DNA damage response RNAs. Scientific Reports 9, 6460 (2019).
303. Mason, J. M. et al. The RAD51-Stimulatory Compound RS-1 Can Exploit the RAD51 Overexpression That Exists in Cancer Cells and Tumors. Cancer Research 74, 3546–3555 (2014). 304. Curtin, N. J. DNA repair dysregulation from
cancer driver to therapeutic target. Nature Reviews Cancer 12, 801–817 (2012).
305. Bryant, E. E., Šunjevarić, I., Berchowitz, L., Rothstein, R. & Reid, R. J. D. Rad5 dysregulation drives hyperactive recombination at replication forks resulting in cisplatin sensitivity and genome instability. Nucleic Acids Research 47, 9144–9159 (2019).
306. Herrero, A. B., San Miguel, J. & Gutierrez, N. C. Deregulation of DNA Double-Strand Break Repair in Multiple Myeloma: Implications for Genome Stability. PLOS ONE 10, e0121581 (2015). 307. Sy, S. M.-H., Guo, Y., Lan, Y., Ng, H. & Huen, M.
S.-Y. Preemptive Homology-Directed DNA Repair Fosters Complex Genomic Rearrangements in Hepatocellular Carcinoma. Translational Oncology 13, 100796 (2020).
308. Åkerfelt, M., Morimoto, R. I. & Sistonen, L. Heat shock factors: integrators of cell stress, development and lifespan. Nature Reviews Molecular Cell Biology 11, 545–555 (2010). 309. Haslbeck, M. & Vierling, E. A First Line of Stress
Defense: Small Heat Shock Proteins and Their Function in Protein Homeostasis. Journal of Molecular Biology 427, 1537–1548 (2015). 310. Njomen, E. & Tepe, J. J. Proteasome Activation
BIB
as a New Therapeutic Approach To TargetProteotoxic Disorders. Journal of Medicinal Chemistry 62, 6469–6481 (2019).
311. Rubinsztein, D. C., Codogno, P. & Levine, B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nature Reviews Drug Discovery 11, 709–730 (2012). 312. Poletto, M. et al. Modulation of proteostasis
counteracts oxidative stress and affects DNA base excision repair capacity in ATM-deficient cells. Nucleic Acids Research 45, 10042–10055 (2017).
313. Ciechanover, A. & Kwon, Y. T. Protein Quality Control by Molecular Chaperones in Neurodegeneration. Frontiers in Neuroscience 11, (2017).
314. Brehme, M. & Voisine, C. Model systems of protein-misfolding diseases reveal chaperone modifiers of proteotoxicity. Disease Models & Mechanisms 9, 823–838 (2016).
315. Soares, T. R., Reis, S. D., Pinho, B. R., Duchen, M. R. & Oliveira, J. M. A. Targeting the proteostasis network in Huntington’s disease. Ageing Research Reviews 49, 92–103 (2019).
316. de Mattos, E. P. et al. Protein Quality Control Pathways at the Crossroad of Synucleinopathies. Journal of Parkinson’s Disease 10, 369–382 (2020). 317. Ciechanover, A. & Kwon, Y. T. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Experimental & Molecular Medicine 47, e147– e147 (2015).
CHAPTER 2
1. Shiloh, Y. & Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nature Reviews Molecular Cell Biology 14, 197–210 (2013).
2. Khanna, K., Lavin, M., Jackson, S. & Mulhern, T. ATM, a central controller of cellular responses to DNA damage. Cell Death & Di erentiation 8, 1052–1065 (2001).
3. McKinnon, P. J. ATM and the Molecular Pathogenesis of Ataxia Telangiectasia. Annual Review of Pathology: Mechanisms of Disease 7, 303–321 (2012).
4. Hipp, M. S., Kasturi, P. & Hartl, F. U. The proteostasis network and its decline in ageing. Nature Reviews Molecular Cell Biology 20, 421– 435 (2019).
5. Kaushik, S. & Cuervo, A. M. Proteostasis and aging. Nature Medicine 21, 1406–1415 (2015). 6. Labbadia, J. & Morimoto, R. I. The Biology
of Proteostasis in Aging and Disease. Annual Review of Biochemistry 84, 435–464 (2015). 7. Hotokezaka, Y., Katayama, I. & Nakamura, T.
ATM-associated signalling triggers the unfolded protein response and cell death in response to stress. Communications Biology 3, 378 (2020). 8. Yan, M. et al. Endoplasmic Reticulum Stress and
Unfolded Protein Response in Atm-Deficient Thymocytes and Thymic Lymphoma Cells Are Attributable to Oxidative Stress. Neoplasia 10, 160–167 (2008).
9. Liu, N. et al. ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes. Laboratory Investigation 85, 1471– 1480 (2005).
10. Wood, L. M. et al. A Novel Role for ATM in Regulating Proteasome-Mediated Protein Degradation through Suppression of the ISG15 Conjugation Pathway. PLoS ONE 6, e16422 (2011). 11. Alexander, A. et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proceedings of the National Academy of Sciences 107, 4153–4158 (2010).
12. Sunderland, P. et al. ATM-deficient neural precursors develop senescence phenotype with disturbances in autophagy. Mechanisms of
Ageing and Development 190, 111296 (2020). 13. Ross, C. A. & Poirier, M. A. Protein aggregation
and neurodegenerative disease. Nature Medicine 10, S10–S17 (2004).
14. Kampinga, H. H. & Bergink, S. Heat shock proteins as potential targets for protective strategies in neurodegeneration. The Lancet Neurology 15, 748–759 (2016).
15. Henning, R. H. & Brundel, B. J. J. M. Proteostasis in cardiac health and disease. Nature Reviews Cardiology 14, 637–653 (2017).
16. Klaips, C. L., Jayaraj, G. G. & Hartl, F. U. Pathways of cellular proteostasis in aging and disease. Journal of Cell Biology 217, 51–63 (2018).
17. Guo, Z., Kozlov, S., Lavin, M. F., Person, M. D. & Paull, T. T. ATM Activation by Oxidative Stress. Science 330, 517–521 (2010).
18. Lee, J.-H. et al. ATM directs DNA damage responses and proteostasis via genetically separable pathways. Science Signaling 11, eaan5598 (2018).
19. Fiévet, A. et al. Three new cases of ataxia-telangiectasia-like disorder: No impairment of the ATM pathway, but S-phase checkpoint defect. Human Mutation 40, 1690–1699 (2019). 20. Taylor, A. M. R., Groom, A. & Byrd, P. J.
Ataxia-telangiectasia-like disorder (ATLD)—its clinical presentation and molecular basis. DNA Repair 3, 1219–1225 (2004).
21. Delia, D. MRE11 mutations and impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia-like disorder. Human Molecular Genetics 13, 2155–2163 (2004). 22. Hirano, R. et al. Spinocerebellar ataxia with
axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation? The EMBO Journal 26, 4732–4743 (2007).
23. Fragola, G. et al. Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration. Nature Communications 11, (2020).
24. Katyal, S. et al. Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes. Nature Neuroscience 17, (2014).
BIB
Mutations in Recessive Spinocerebellar AtaxiaAssociated with Pediatric Onset Drug Resistant Epilepsy and Intellectual Disability (SCAR23). The Cerebellum 18, 972–975 (2019).
26. Zagnoli-Vieira, G. et al. Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23). Neurology Genetics 4, e262 (2018).
27. Petr, M. A., Tulika, T., Carmona-Marin, L. M. & Scheibye-Knudsen, M. Protecting the Aging Genome. Trends in Cell Biology 30, 117–132 (2020). 28. Shiloh, Y. The cerebellar degeneration in ataxia-telangiectasia: A case for genome instability. DNA Repair 95, 102950 (2020).
29. Zheng, J., Croteau, D. L., Bohr, V. A. & Akbari, M. Diminished OPA1 expression and impaired mitochondrial morphology and homeostasis in Aprataxin-deficient cells. Nucleic Acids Research
47, 4086–4110 (2019).
30. Richard, P. et al. SETX (senataxin), the helicase mutated in AOA2 and ALS4, functions in autophagy regulation. Autophagy 1–18 (2020) doi:10.1080/15548627.2020.1796292.
31. Gilbert, D. C., Chalmers, A. J. & El-Khamisy, S. F. Topoisomerase I inhibition in colorectal cancer: biomarkers and therapeutic targets. British Journal of Cancer 106, 18–24 (2012).
32. Pommier, Y., Leo, E., Zhang, H. & Marchand, C. DNA Topoisomerases and Their Poisoning by Anticancer and Antibacterial Drugs. Chemistry & Biology 17, 421–433 (2010).
33. Conlon, E. G. & Manley, J. L. RNA-binding proteins in neurodegeneration: mechanisms in aggregate. Genes & Development 31, 1509–1528 (2017).
34. Geiger, T., Wehner, A., Schaab, C., Cox, J. & Mann, M. Comparative Proteomic Analysis of Eleven Common Cell Lines Reveals Ubiquitous but Varying Expression of Most Proteins. Molecular & Cellular Proteomics 11, M111.014050 (2012).
35. Dobson, C. M. Principles of protein folding, misfolding and aggregation. Seminars in Cell & Developmental Biology 15, (2004).
36. Zapadka, K. L., Becher, F. J., Gomes dos Santos, A. L. & Jackson, S. E. Factors affecting the physical stability (aggregation) of peptide
therapeutics. Interface Focus 7, (2017).
37. Vendruscolo, M., Knowles, T. P. J. & Dobson, C. M. Protein Solubility and Protein Homeostasis: A Generic View of Protein Misfolding Disorders. Cold Spring Harbor Perspectives in Biology 3, a010454–a010454 (2011).
38. Lin, Y., Protter, D. S. W., Rosen, M. K. & Parker, R. Formation and Maturation of Phase-Separated Liquid Droplets by RNA-Binding Proteins. Molecular Cell 60, 208–219 (2015).
39. Wang, J. et al. A Molecular Grammar Governing the Driving Forces for Phase Separation of Prion-like RNA Binding Proteins. Cell 174, 688-699.e16 (2018).
40. Kanaan, N. M., Hamel, C., Grabinski, T. & Combs, B. Liquid-liquid phase separation induces pathogenic tau conformations in vitro. Nature Communications 11, 2809 (2020).
41. Peskett, T. R. et al. A Liquid to Solid Phase Transition Underlying Pathological Huntingtin Exon1 Aggregation. Molecular Cell 70, 588-601. e6 (2018).
42. Molliex, A. et al. Phase Separation by Low Complexity Domains Promotes Stress Granule Assembly and Drives Pathological Fibrillization. Cell 163, 123–133 (2015).
43. Martin, E. W. & Mittag, T. Relationship of Sequence and Phase Separation in Protein Low-Complexity Regions. Biochemistry 57, 2478– 2487 (2018).
44. Mitchell, S. F., Jain, S., She, M. & Parker, R. Global analysis of yeast mRNPs. Nature Structural & Molecular Biology 20, (2013).
45. Alberti, S. & Dormann, D. Liquid–Liquid Phase Separation in Disease. Annual Review of Genetics
53, (2019).
46. Linding, R., Schymkowitz, J., Rousseau, F., Diella, F. & Serrano, L. A Comparative Study of the Relationship Between Protein Structure and β-Aggregation in Globular and Intrinsically Disordered Proteins. Journal of Molecular Biology 342, (2004).
47. Fernandez-Escamilla, A.-M., Rousseau, F., Schymkowitz, J. & Serrano, L. Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins. Nature Biotechnology 22, (2004).
