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Nucleotide Excision Repair in Eukaryotes Downloaded from http://cshperspectives.cshlp.org/ on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Nucleotide Excision Repair in Eukaryotes Orlando D. Scha¨rer Department of Pharmacological Sciences and Department of Chemistry, Stony Brook University, Stony Brook, New York 11974-3400 Correspondence: [email protected] Nucleotide excision repair (NER) is the main pathway used by mammals to remove bulky DNA lesions such as those formed by UV light, environmental mutagens, and some cancer chemotherapeutic adducts from DNA. Deficiencies in NER are associated with the ex- tremely skin cancer-prone inherited disorder xeroderma pigmentosum. Although the core NER reaction and the factors that execute it have been known for some years, recent studies have led to a much more detailed understanding of the NER mechanism, how NER operates in the context of chromatin, and how it is connected to other cellular processes such as DNA damage signaling and transcription. This review emphasizes biochemical, structural, cell biological, and genetic studies since 2005 that have shed light on many aspects of the NER pathway. ucleotide excision repair (NER) is the main ing NER. These two steps were observed in the Npathway responsible for the removal of earliest studies of NER in bacteria and humans, bulky DNA lesions induced by UV irradiation, respectively, in 1964 and marked the begin- environmental mutagens, and certain chemo- nings of NER research 50 years ago (Boyce and therapeutic agents. The history of the discovery Howard-Flanders 1964; Pettijohn and Hanawalt of NER, its association with genetic disorders, 1964; Rasmussen and Painter 1964; Setlow and mechanistic features, and relationship with oth- Carrier 1964). The gap-filling step in NER can er cellular pathways has been extensively re- be monitored by unscheduled DNA synthesis viewed in 2005 in several articles in DNA Repair (UDS), and this assay allowed the connection and Mutagenesis (Friedberg et al. 2005). Here, I between NER and the genetic disorder xeroder- will briefly reiterate how the field of NER devel- ma pigmentusum (XP) to be made (Cleaver oped over the past 50 years and then focus on 1968). UDS is used to date in the clinical diag- how our knowledge has progressed since 2005. nosis of XP patients and was instrumental in the elucidation of the NER pathway. XP patients display an extreme sensitivity to sunlight and A BRIEF HISTORY OF NER RESEARCH an over 2000-fold increased risk of skin cancer, We now know that a short damage-containing as they are unable to repair lesions induced by oligonucleotide is released from DNA and the solar UV irradiation in their skin (DiGiovanna resulting gap filled during repair synthesis dur- and Kraemer 2012). At least two other disor- Editors: Errol C. Friedberg, Stephen J. Elledge, Alan R. Lehmann, Tomas Lindahl, and Marco Muzi-Falconi Additional Perspectives on DNA Repair, Mutagenesis, and Other Responses to DNA Damage available at www.cshperspectives.org Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a012609 Cite this article as Cold Spring Harb Perspect Biol 2013;5:a012609 1 Downloaded from http://cshperspectives.cshlp.org/ on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press O.D. Scha¨rer ders, Cockayne syndrome and trichothiodystro- In the following sections, I will discuss our phy (TTD), are also associated with defects in current understanding of the NER process in NER genes; but these patients do not present the order in which the steps occur, followed with skin cancer predisposition, but rather a by the connection to chromatin structure and host of developmental and neurological abnor- DNA damage signaling. The reader is referred malities (Lehmann 2003). These symptoms are to other reviews in this collection that cover generally ascribed to a defect in transcription- NER in bacteria (Kisker et al. 2013) and tran- coupled NER and a mild or partial defect in scription-coupled NER (Vermeulen and Fous- transcription. teri 2013). Studies of XP patient cell lines then revealed that UDS varied significantly among cell lines. THE CORE NER REACTION Using cell fusion techniques, it was established that seven complementation groups with NER Different Modes of Damage defects exist, XPA through XPG, each represent- Recognition in NER ing a different gene defect (De Weerd-Kastelein NERcan be initiated by two subpathways: global et al. 1972). The availability of the XP cell lines genome NER (GG-NER) or transcription-cou- from patients, along with UV-sensitive yeast pled NER (TC-NER; Gillet and Scha¨rer 2006; strains (Prakash and Prakash 2000) and Chinese Hanawalt and Spivak 2008). GG-NER can occur hamster ovary cell lines (Thompson 1998), anywhere in the genome, whereas TC-NER is made it possible to clone the NER genes over responsible for the accelerated repair of lesions the years (Gillet and Scha¨rer 2006). in the transcribed strand of active genes. GG- The next phase of discovery was facilitated NER is initiated by the GG-NER specific factor by the development of assays of studying NER XPC-RAD23B, in some cases with the help of in cell-free extracts by either monitoring in- UV-DDB (UV-damaged DNA-binding pro- corporation of radioactive deoxynucleotide tri- tein). TC-NER is initiated by RNA polymerase phosphates (dNTPs) into damage-containing stalled at a lesion with the help of TC-NER spe- plasmids during repair synthesis (Wood et al. cific factors CSA, CSB, and XAB2. Both path- 1988) or the excision of the labeled damage-con- ways require the core NER factors to complete taining oligonucleotide from a larger DNA frag- the excision process. Very recently, an additional ment (Huang et al. 1992). In the mid-1990s, the class of enzymes, the alkyltransferase-like (ATL) use of these assays culminated in the reconstitu- proteins, have been shown to channel bulky tion of the NER reaction with purified factors O6-alkylguanine lesions into the NER pathway, (Aboussekhra et al. 1995; Mu et al. 1995; Araujo at least in some lower eukaryotes and bacteria et al. 2000). These studies revealed that the pro- (Tubbs et al. 2009; Latypov et al. 2012). ATLs cess also required proteins involved in replica- bind to these bulky alkyl lesion and facilitate tion, such as the single-stranded DNA- (ssDNA) their removal from DNA in an NER-dependent binding protein RPA, the clamp loader PCNA, fashion. There is no other described repair path- and polymerase d. Biochemically derived mod- way for bulky O6-alkylguanine lesions in hu- els of NER received strong support from sub- mans, so it will be interesting to uncover wheth- sequent cell biological studies using UV ir- er an analogous pathway exists in mammals. radiation through filters to generate sites of localized damage in cell nuclei in combination Substrate Specificity of Nucleotide with green fluorescent protein-labeled proteins Excision Repair or immunohistological techniques to monitor the dynamic behavior of NER proteins (Houts- A key characteristic of the NER pathway is that muller et al. 1999; Volker et al. 2001). These one set of enzymes can recognize an extraordi- studies revealed that NER functions through narily wide range of substrates, including UV- the sequential and coordinated assembly of induced photoproducts (cyclopyrimidine di- the factors involved at the sites of UV damage. mers [CPDs], 6-4 photoproducts [6-4PPs]), 2 Cite this article as Cold Spring Harb Perspect Biol 2013;5:a012609 Downloaded from http://cshperspectives.cshlp.org/ on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Nucleotide Excision Repair in Eukaryotes adducts formed by environmental mutagens Structural studies of the yeast homolog of such as benzo[a]pyrene or various aromatic XPC, Rad4, have provided a high-resolution amines, certain oxidative endogenous lesions view of how this is accomplished. XPC/Rad4 such as cyclopurines and adducts formed by has two main functional domains (Min and cancer chemotherapeutic drugs such as cis- Pavletich 2007): a lesion and sequence-unspe- platin (Friedberg et al. 2005; Gillet and Scha¨rer cific DNA-binding domain made up of a trans- 2006). Although these lesions do not share glutamase homology domain and a b-hairpin chemical structures that would lend themselves domain (BHD1) (blue in Fig. 2A) anchors the to a common lesion-binding pocket, a collec- protein on the DNA. A double b-hairpin do- tive feature of good NER substrates is that they main (BHD2/3, pink in Fig. 2A) binds the un- thermodynamically destabilize the DNA duplex damaged strand of the DNA without making and are bulky. These properties were originally direct contact with the lesion, which is disor- framed in the context of the bipartite recogni- dered in this structure. Instead, BHD2/3 encir- tion model that posits that good NER substrates cles two nucleotides opposite the damage that are destabilizing and bulky (Hess et al. 1997). display increased ssDNA character due to the Subsequent studies correlating the structures thermodynamic destabilization caused by the of adducts such as those formed by benzo[a]- lesion. This binding pocket is specific for non- pyrene or acetylaminofluorene with their repair damaged DNA and it would not be able to ac- efficiencies confirmed these observations and commodate bulky DNA adducts. Therefore, showed that factors such as disrupted base-pair- XPC is necessarily targeted to the nondamaged ing, bending, and flexibility can contribute to DNA strand. This mode of DNA binding makes repair outcomes (Mocquet et al. 2007; Cai et al. it possible for XPC to bind a wide variety of 2010; Mu et al. 2012; Yeo et al. 2012). As dis- structurally diverse bulky lesions, in keeping cussed in the next section, we now understand the broad substrate specificity of NER (Huang these principles in terms of how damage recog- et al.
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