Post-incision events induced by UV : regulation of incision and the role of post-incision factors in mammalian NER Overmeer, R.M.

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Post-incision events induced by UV : regulation of incision and the role of post-incision factors in mammalian NER

Overmeer, R.M.

Citation

Overmeer, R. M. (2010, September 29). Post-incision events induced by UV : regulation of incision and the role of post-incision factors in mammalian NER.

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Introduction

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Chapter 1: Introduction

DNA damage and repair

Our genome contains all the information required for cells to function thus providing the basis to function as an organism. The integrity of our genome is therefore essential, however, on top of the intrinsic chemical instability of DNA, our genome is continuously damaged by genotoxic agents coming from both exogenous and endogenous sources. For instance, it has been estimated that endogenous sources, per cell, alone create approximately 1000 single strand breaks (SSBs) and oxidative damages per hour (Vilenchik and Knudson, 2003). In addition, exogenous sources such as sunlight are known to induce DNA damage such as pyrimidine-(6-4)-pyrimidone photoproducts (6-4PPs) and cyclobutane pyrimidine dimers (CPDs) in the skin. In al living organisms, effi cient repair mechanisms that are able to remove such damages, are essential to maintain the integrity of the genome. Five major pathways able to repair a broad variety of DNA damages have been identifi ed: homologous recombination (HR), nonhomologous end-joining (NHEJ), mismatch repair (MMR), base excision repair (BER) and nucleotide excision repair (NER) (Figure1) (Hoeijmakers, 2001). The importance of these repair mechanisms is emphasized by human syndromes resulting from defects in genes encoding for the factors involved. Impairment of any of these pathways leads to an increased sensitivity to DNA damaging agents and cancer susceptibility, in addition to developmental and neurological abnormalities.

Of particular interest is NER, which is able to recognize and repair a broad spectrum of particularly bulky helix distorting DNA lesions, either induced endogenously or exogenously by physical and chemical agents including radiation (particularly UV) and various mutagenic chemicals. This broad substrate recognition is achieved by two distinct subpathways of NER, which are triggered by recognition of the consequences of the lesion (i.e. structural and me- chanistic) as opposed to direct recognition of the lesion itself. The fi rst, global genome NER (GG-NER), is able to repair lesions throughout the entire genome through recognition of the reduced rigidity resulting from the helix distortion (Yang, 2008). The second, transcription coupled NER (TC-NER), specifi cally repairs lesions which block transcription. After recognition both pathways are identical and the removal of the damage is accomplished by excising a ~30bp fragment of DNA surrounding the lesion (Figure 2), thereby maintaining the capacity to repair a broad spectrum of DNA damage (Gillet and Scharer, 2006).

NER associated diseases

NER is a multiprotein process that requires over 30 proteins to carry out DNA damage recognition, excision of the damage, gapfi lling by DNA replication, ligation and fi nal resto- ration of chromatin structure. Defects in genes encoding for these proteins lead to the rare autosomal inherited diseases xeroderma pigmentosum (XP), Cockayne Syndrome (CS) or triochothiodystrophy (TTD); for an overview of the factors involved in NER, their general function and, where appropriate, the corresponding diseases see Table 1. XP is characterized

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13 by an extreme sensitivity to sunlight and a 1000-fold increased risk of developing cancer in sun exposed parts of the body. In addition one in fi ve patients suffers from neural degene- ration. Eight complementation groups have been found in XP patients, the fi rst 7 (XP-A to XP-G) are either defective in GG-NER exclusively, or in both GG-NER and TC-NER. The last complementation group (XP-V) is defective in DNA polymerase η (Polη), a translesion polymerase involved in lesion bypass during replication. In addition to UV sensitivity, CS patients have severe neurological abnormalities, short stature, bird-like features, tooth de- cay, cataracts and a shortened life expectancy of 12.5 years. There are two complementation groups in CS (CS-A and CS-B) both are defective in TC-NER whilst GG-NER is profi cient.

TTD patients also consist of two groups; photosensitive TTD and non-photosensitive TTD.

Both groups share symptoms with CS patients with, in addition, brittle hair and scaling of the skin, with the exception of UV sensitivity in non-photosensitive TTD patients. All proteins encoded by the genes mutated in photosensitive TTD (XPB, XPD and TTDA) are part of the transcription complex TFIIH. Cells from TTD patients have a signifi cantly reduced amount of TFIIH in addition, mutations underlying photosensitive TTD lead to signifi cantly lower basal transcription levels in vitro (Botta et al., 2002; Dubaele et al., 2003; Vermeulen et al.,

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Xeroderma Pigmentosum

Patient group Function Subpathway Disease Genetic defect

XPA Damage verifi cation, XPF recruitment and RPA orientation

TC-NER &

GG-NER

XP XPA gene

(9q34.1) XPB 3’-5’ Helicase and ATPase. Part of the

10-subunit protein complex TFIIH.

TC-NER &

GG-NER

XP, XP/CS, TTD

XPB gene (2q21)

XPC Sensing helix distortion GG-NER XP XPC gene

(3p25.1) XPD 5’-3’ Helicase and ATPase, required for

damage verifi cation. Part of the 10-subunit protein complex TFIIH.

TC-NER &

GG-NER

XP, XP/CS, TTD

XPD gene (19q13.2)

XPE Sensing helix distortion (also within chromatin), E3 Ubiquitin ligase

GG-NER XP DDB2 gene

(11q12-q13)

XPF 5’ Exonuclease TC-NER &

GG-NER

XP XPF or

ERCC1 genes

XPG 3’ Exonuclease TC-NER &

GG-NER

XP, XP/CS XPG gene

XP-Variant Gap fi lling TLS polymerase (polη) GG-NER XP, UV-sensitive

DNA polymerase η gene Cockayne Syndrome

CSA DNA-dependent ATP-ase and chromatin remodelling

TC-NER CS CSA gene

CSB Recruitment CSA and E3 Ubiquitin ligase TC-NER CS CSB gene

Triochothiodystrophy

TTDA TFIIH stability and ATPase regulation - TTD TTDA

TTDN1 Plays a role in mitosis and cytokinesis - TTD TTDN1

Table 1. Overview of the NER associated diseases, the involved proteins and their function.

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2000). Therefore defects in transcription and transcription associated processes are thought to underlie many of the symptoms seen in TTD (Cleaver, 2005). In contrast, the genetic defects underlying non-photosensitive TTD are mostly unknown with TTDN1 mutations being found in only 6 of the 44 unrelated patients.TTDN1 patients are not defective in NER and appear to have normal TFIIH levels. TTDN1 interacts with polo-like kinase 1 and plays a role in regulating mitosis and cytokinesis (Botta et al., 2007; Zhang et al., 2007). The observation that neurological problems in TTD patients stem more from developmental defects than from neurodegeneration, together with the implicated transcriptional, mitosis and cytokinesis defects, suggests that the phenotype arises from defective developmental regulation (Hashimoto and Egly, 2009; Brooks et al., 2008).

TC-NER

Active TC-NER leads to a rapid repair of transcribed regions and its main function is to en- sure continuous transcription and to counteract mutagenesis. TC-NER thereby prevents mutagenesis both directly and indirectly, as transcription of damaged DNA has been shown to increase mutagenesis (Hendriks et al., 2008). As TC-NER is not the main topic of this thesis and both the history of TC-NER research as TC-NER itself have been reviewed recently (Ha- nawalt and Spivak, 2008; Fousteri and Mullenders, 2008; Tornaletti, 2009) the transcription mediated initiation of NER will only be discussed briefl y.

Multiple RNA polymerases are active in mammalian cells however, only RNA Poly- merase II (RNAPII) has been shown so far to initiate TC-NER. CSB interacts dynamically with the transcription machinery and has been shown to be involved in transcriptional regulation (Kyng et al., 2003; Proietti-De-Santis et al., 2006). Stalling of RNAPII leads to an increased binding of CSB (van den Boom et al., 2004), which in turn recruits other factors required for TC-NER such as CSA and the pre-incision factors shared by GGR (Fousteri et al., 2006). Although CSA and CSB patients share similar phenotypes the proteins function in a different manner. Whereas CSB enables the recruitment of pre-incision factors, enabling unwinding of the DNA, damage verifi cation and incision (discussed later), CSA apparently has no direct role in recruitment of NER pre-incision factors in TC-NER (Fousteri and Mul- lenders, 2008). CSA is required for the recruitment of HMGN1 and TFIIS to sites of stalled transcription, moreover the recruitment of XAB2 is also dependent on the CS factors, most probably through CSA (Fousteri et al., 2006; Neer et al., 1994). In addition to recruiting factors involved in transcriptional reinitiation, CSA is also part an E3-Ubiquitin ligase complex (containing DDB1, Cullin4a and ROC1/Rbx1) (Groisman et al., 2003). Data suggest that the COP9 signalosome inhibits its ligase activity at early time points after UV (Fousteri et al., 2006; Groisman et al., 2003). Although it is known that HMGN1 defi ciency leads to impaired TC-NER and that HMGN1 modulates posttranslational modifi cation of H3, its exact role in TC-NER in unclear (Birger et al., 2003; Lim et al., 2005). Similarly XAB2 has been shown to interact with XPA, chromatin and stalled RNAPII and knock-down led to a reduced RNA synthesis recovery, yet its role remains to be determined (Nakatsu et al., 2000; Kuraoka et al.,

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15 2008).

Although several studies suggest that TC-NER initiates without the displacement of RNAPII, it is generally assumed that RNAPII can be displaced to enable the repair of a subset of lesions. This idea is supported by the observation, that in complexes stalled by a CPD, the lesion is within the footprint of RNAPII (Tornaletti and Hanawalt, 1999; Selby et al., 1997;

Mei Kwei et al., 2004). There are two postulated mechanisms to uncover the lesion, the fi rst is NEDD4 dependent ubiquitination and subsequent proteosomal degradation of RNAPII (Anindya et al., 2007; Malik et al., 2008), the second is reverse translocation (i.e. backtracking). In the case of backtracking the RNA polymerase reverses on the DNA and RNA subsequently the 3’end of the mRNA is no longer present in the active site. As the 3’end is required for elongation of the transcript the excess RNA prevents reinitiation of transcription (Hanawalt, 2007). The elongation factor TFIIS, recruited in a CSA dependent manner, is able to initiate RNAPII mediated cleavage of the mRNA, re-establishing the 3’end in the active site of RNAPII and enabling the restart of transcription (Kalogeraki et al., 2005). In the alter- native, RNAPII is ubiquitinated and subsequently degraded. Although the CSA E3-ubiquitin ligase activity would be an obvious contender for this ubiquitination, it has been shown that Nedd4 is the ubiquitin ligase and that the CS proteins only function indirectly (Anindya et al., 2007). Degradation of RNAPII would remove the stalled complex from the DNA and thereby clearing the path for following transcription complexes. As there is data supporting both modes of lesions clearance it is conceivable that both mechanisms can occur in mammalian cells. It would be interesting to uncover how and under which conditions these separate mechanisms of RNAPII displacement are regulated.

As mentioned before CSA and CSB patients share similar phenotypes yet the CSA and CSB proteins have distinct roles. In short CSB is required for initiation of TC-NER and therefore removal of the damage, whereas CSA is, indirectly, involved in the reinitiation of transcription after repair. Defects in either gene would lead to permanently stalled transcription complexes, explaining the defective RNA synthesis recovery observed in CS cells (Fousteri and Mullenders, 2008).

GG-NER

Whereas TC-NER is able to repair transcription blocking lesions GG-NER is able to repair helix distorting lesions throughout the entire genome. Although GG-NER is able to repair lesion throughout the entire genome the actual repair rate differs per region. For example regions with active transcription have a higher TC-NER independent repair rate, as demon- strated by the non-transcribed strand having a higher repair rate than genome overall (Bielas, 2006; Nouspikel et al., 2006). This higher repair rate is thought to be caused by the less condense packaging of the chromatin, which would lead to increased accessibility to repair factors. In support of this, relaxation of the chromatin, either through demethylation or acetylation, increases the repair rate throughout the genome (Ho et al., 1989; Ramanathan and Smerdon, 1989). Concomitantly the SWI/SNF chromatin remodeler has been found to be

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required for effi cient repair (Hara and Sancar, 2002). In short one can distinguish a hierarchy of repair rate, with the compact transcriptionally inactive heterochromatin having the lowest repair rate and the repair being somewhat faster in the less compact euchromatin, often due to transcription. Finally the transcribed strand has the highest repair rate due to the dedica- ted subpathway, TC-NER. Although GG-NER is highly conserved throughout evolution, the actual level of repair can differ between different types of cells as various terminally differentiated cells show low levels of NER (Hsu et al., 2007; Jensen and Linn, 1988; Nouspikel and Hanawalt, 2000; Tofi lon and Meyn, 1988), although this doesn’t hold for all cell types as both non-dividing rat myocytes and dividing fi broblasts exhibited effi cient NER (van der Wees et al., 2003). However, this downregulation of repair is not only seen in cells that no longer need to replicate their DNA as some quiescent cells, such as growth arrested mouse embryo fi broblasts, also show lower levels of NER (Bielas, 2006). The expression levels of DDB2 other NER factors has been shown to correlate NER effi ciency (Pines et al., 2009) and offers an explanation for some of the heterogeneity found. However, it is unlikely that this would underlie all the heterogeneity found. Although it is not quite clear what else underlies inter cell type heterogeneity, the ubiquitin pathway has been implicated (Nouspikel and Ha- nawalt, 2006).

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17

o UV light,

Polycyclic aromatic hydrocarbons

Alkylating agents

Reactive oxygen

species X - rays Chemotheraputics Replication errors

NER

(Nucleotide Excision Repair)

BER

(Base Excision Repair)

HR & NHEJ

(Homologous Recombination &

Non - Homologous End - Joining)

MMR

(Mismatch Repair) Bulkyadduct

6 - 4pp CPD

Uracil Single - strand break

Abasic site 8 - oxoguanine

Interstrand cross - link Double - strand break

Mismatch Insertion/deletion

Figure 1. A schematic overview of sources of DNA damage, damages induced and the main method of repair.

P OH

XPC HR23b

TFIIH XPG

XPF ERCC1

XPC TFIIH

XPA

XPG XPF

ERCC1

HR23b

RPA

RPA XPC

HR23b

UV-DDB

RNA Pol CSB

CSA

XPA

Damage recognition

Pre-incision complex formation

Dual incision RPA remains bound Centrin

Centrin

TFIIS XAB2

HMGN1 Centrin

Centrin

Figure 2. NER model describing events leading from recognition to incision.

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