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• W2169385246 abstract "In this issue of Structure, Das et al. report the structure of the helix-hairpin-helix dimerization domain of XPF bound to ssDNA. These results provide insight into the architecture of nucleotide excision repair machinery and how it interacts with damaged DNA substrates. In this issue of Structure, Das et al. report the structure of the helix-hairpin-helix dimerization domain of XPF bound to ssDNA. These results provide insight into the architecture of nucleotide excision repair machinery and how it interacts with damaged DNA substrates. Exposure to natural radiation and industrial pollutants present in our environment damages DNA. Left unresolved, DNA damage can lead to genomic instability and disease. In response, cells have developed an arsenal of DNA repair pathways to identify and eliminate DNA damage. Nucleotide excision repair (NER) is the primary mechanism employed by both prokaryotic and eukaryotic cells to identify and remove bulky chemical modifications in DNA. In humans, defects in NER result in Xeroderma pigmentosum (XP), a spectrum of disorders characterized by extreme sensitivity to UV radiation and an approximately 1,000-fold increase in the development of skin cancers. Additionally, the most severe XP patients display neurodegeneration and dramatically reduced lifespan, underscoring the critical role NER plays in human health (reviewed in Nouspikel, 2009Nouspikel T. Cell. Mol. Life Sci. 2009; 66: 994-1009Crossref PubMed Scopus (246) Google Scholar). NER is a multi-step process that occurs in four phases: (1) damage recognition, (2) unwinding of the DNA and lesion verification, (3) dual incision, and (4) gap-filling synthesis and ligation. In humans, NER requires the coordinated activity of over 30 proteins that, together, constitute the dynamic machinery that repairs the damage. Biochemical studies have revealed NER proceeds as an orchestrated series of events involving a complicated network of protein-protein and protein-DNA interactions (Riedl et al., 2003Riedl T. Hanaoka F. Egly J.M. EMBO J. 2003; 22: 5293-5303Crossref PubMed Scopus (345) Google Scholar). However, a dearth of structural knowledge significantly limits our understanding of the molecular mechanisms of this versatile repair machinery. Human NER proteins have proven particularly resistant to structural characterization, and a lack of conservation between prokaryotic and eukaryotic NER proteins limits translation of mechanistic insight from bacterial systems where NER is better characterized. Each step in the NER process is marked by changes in the structure of the DNA substrate and remodeling of the repair machinery. Prior to the excision phase, a region of approximately 30 basepairs of DNA surrounding the lesion is unwound, generating an intermediate known as the pre-incision bubble (Riedl et al., 2003Riedl T. Hanaoka F. Egly J.M. EMBO J. 2003; 22: 5293-5303Crossref PubMed Scopus (345) Google Scholar). XPF and XPG are structure-specific nucleases, and their positioning on the DNA substrate is imperative for their proper function. The XPF-ERCC1 complex is the final repair factor loaded onto the DNA substrate, and cleavage at the 5′ junction by XPF is required for the subsequent 3′ cleavage event by XPG (Staresincic et al., 2009Staresincic L. Fagbemi A.F. Enzlin J.H. Gourdin A.M. Wijgers N. Dunand-Sauthier I. Giglia-Mari G. Clarkson S.G. Vermeulen W. Schärer O.D. EMBO J. 2009; 28: 1111-1120Crossref PubMed Scopus (187) Google Scholar). Even though a substantial amount of structural information has accumulated for XPF-ERCC1 (Newman et al., 2005Newman M. Murray-Rust J. Lally J. Rudolf J. Fadden A. Knowles P.P. White M.F. McDonald N.Q. EMBO J. 2005; 24: 895-905Crossref PubMed Scopus (99) Google Scholar, Tripsianes et al., 2005Tripsianes K. Folkers G. Ab E. Das D. Odijk H. Jaspers N.G. Hoeijmakers J.H. Kaptein R. Boelens R. Structure. 2005; 13: 1849-1858Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, Tripsianes et al., 2007Tripsianes K. Folkers G.E. Zheng C. Das D. Grinstead J.S. Kaptein R. Boelens R. Nucleic Acids Res. 2007; 35: 5789-5798Crossref PubMed Scopus (37) Google Scholar, Tsodikov et al., 2005Tsodikov O.V. Enzlin J.H. Schärer O.D. Ellenberger T. Proc. Natl. Acad. Sci. USA. 2005; 102: 11236-11241Crossref PubMed Scopus (137) Google Scholar, Tsodikov et al., 2007Tsodikov O.V. Ivanov D. Orelli B. Staresincic L. Shoshani I. Oberman R. Schärer O.D. Wagner G. Ellenberger T. EMBO J. 2007; 26: 4768-4776Crossref PubMed Scopus (117) Google Scholar), exactly how it engages DNA and the molecular basis for the polarity of XPF/ERCC1 binding to the NER bubble remain unknown. In this issue of Structure, Das et al., 2012Das D. Folkers G.E. van Dijk M. Jaspers N.G.J. Hoeijmakers J.H.J. Kaptein R. Boelens R. Structure. 2012; 20 (this issue): 667-675Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar report the structure of the C-terminal dimerization domain of XPF in complex with ssDNA, which provides the basis for a refined model of how and where XPF-ERCC1 binds the NER bubble. Although structures of various XPF and ERCC1 domains have been reported, insight into how the complex interacts with DNA has been limited. The three-dimensional structures of crenarcheal XPF in the absence and presence of DNA have been determined; however, this protein lacks an analog to ERCC1 and functions as a homodimer (Newman et al., 2005Newman M. Murray-Rust J. Lally J. Rudolf J. Fadden A. Knowles P.P. White M.F. McDonald N.Q. EMBO J. 2005; 24: 895-905Crossref PubMed Scopus (99) Google Scholar). Models proposed for XPF-ERCC1 binding to the NER bubble were based on the available structures, homology to other proteins that bind DNA with helical hairpins (Singh et al., 2002Singh S. Folkers G.E. Bonvin A.M. Boelens R. Wechselberger R. Niztayev A. Kaptein R. EMBO J. 2002; 21: 6257-6266Crossref PubMed Scopus (39) Google Scholar), reports showing that both ssDNA and dsDNA bind to ERCC1 in the XPF-ERCC1 heterodimer (Tripsianes et al., 2005Tripsianes K. Folkers G. Ab E. Das D. Odijk H. Jaspers N.G. Hoeijmakers J.H. Kaptein R. Boelens R. Structure. 2005; 13: 1849-1858Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, Tripsianes et al., 2007Tripsianes K. Folkers G.E. Zheng C. Das D. Grinstead J.S. Kaptein R. Boelens R. Nucleic Acids Res. 2007; 35: 5789-5798Crossref PubMed Scopus (37) Google Scholar, Tsodikov et al., 2005Tsodikov O.V. Enzlin J.H. Schärer O.D. Ellenberger T. Proc. Natl. Acad. Sci. USA. 2005; 102: 11236-11241Crossref PubMed Scopus (137) Google Scholar), and an NMR chemical shift perturbation study that mapped the binding site for dsDNA to the two helical hairpins of ERCC1 in the XPF-ERCC1 complex (Tripsianes et al., 2005Tripsianes K. Folkers G. Ab E. Das D. Odijk H. Jaspers N.G. Hoeijmakers J.H. Kaptein R. Boelens R. Structure. 2005; 13: 1849-1858Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). However, these previous models were limited by the absence of explicit information on ssDNA binding to XPF-ERCC1. A key finding in the new structure described by Das et al., 2012Das D. Folkers G.E. van Dijk M. Jaspers N.G.J. Hoeijmakers J.H.J. Kaptein R. Boelens R. Structure. 2012; 20 (this issue): 667-675Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar was that a one residue deletion in the non-canonical HhH motif in XPF alters the DNA binding such that ssDNA is preferred over the dsDNA binding typical of canonical HhH domains (Shao and Grishin, 2000Shao X. Grishin N.V. Nucleic Acids Res. 2000; 28: 2643-2650Crossref PubMed Scopus (113) Google Scholar). This is an excellent example of the powerful effect that very subtle structural effects can have on biochemical function. The fact that this change is due to such a small alteration in sequence highlights the importance of determining structures for discerning mechanism. Most importantly, the structure provides a direct explanation for how XPF/ERCC1 binds at ssDNA/dsDNA junctions. This led directly to a model that explains the polarity of binding and, therefore, why XPF is directed to the 5′ junction. Whereas the authors' structural model for XPF-ERCC1 binding the 5′ ssDNA/dsDNA junction is compelling, it also raises a number of questions about the global architecture of the multi-protein NER complex that assembles on the pre-incision bubble. Replication protein A (RPA) is known to play a critical role in organizing assembly of the NER machinery and coordinating access to the DNA substrate (Riedl et al., 2003Riedl T. Hanaoka F. Egly J.M. EMBO J. 2003; 22: 5293-5303Crossref PubMed Scopus (345) Google Scholar). In vitro NER studies have demonstrated that ∼30 nucleotides of ssDNA are liberated by dual excision (Moggs et al., 1996Moggs J.G. Yarema K.J. Essigmann J.M. Wood R.D. J. Biol. Chem. 1996; 271: 7177-7186Crossref PubMed Scopus (182) Google Scholar). This corresponds to the approximate footprint of a single RPA molecule bound to the unmodified strand opposite the lesion. In the authors' model, the binding of XPF to ssDNA on the undamaged strand could lead to a clash with RPA (Figure 1), which binds ssDNA much more tightly than XPF-ERCC1 and remains associated with the unmodified strand through the transition to gap-filling synthesis (Riedl et al., 2003Riedl T. Hanaoka F. Egly J.M. EMBO J. 2003; 22: 5293-5303Crossref PubMed Scopus (345) Google Scholar). Therefore, it remains to be determined how binding of XPF-ERCC1 to the 5′ junction influences the binding of RPA to the template strand. On the other hand, the authors' conclusion that XPF-ERCC1 binds to the 5′ junction has important implications for the positioning of XPA in the pre-incision bubble. XPA binds to ssDNA/dsDNA junctions, but it is has yet to be determined which junction XPA binds in the pre-incision bubble (Krasikova et al., 2010Krasikova Y.S. Rechkunova N.I. Maltseva E.A. Petruseva I.O. Lavrik O.I. Nucleic Acids Res. 2010; 38: 8083-8094Crossref PubMed Scopus (54) Google Scholar). Because XPA is believed to recruit XPF-ERCC1 to the NER machinery via interaction with the central domain of ERCC1 (Tsodikov et al., 2007Tsodikov O.V. Ivanov D. Orelli B. Staresincic L. Shoshani I. Oberman R. Schärer O.D. Wagner G. Ellenberger T. EMBO J. 2007; 26: 4768-4776Crossref PubMed Scopus (117) Google Scholar), it has been proposed that XPA binds to the 5′ junction. However, in the authors' model, XPF-ERCC1 occludes the entire junction. If XPA were bound to the 5′ junction, XPF-ERCC1 would have to displace XPA from the DNA to gain access to the substrate (Figure 1A). This seems unlikely, as XPA remains associated with the NER machinery throughout excision repair (Riedl et al., 2003Riedl T. Hanaoka F. Egly J.M. EMBO J. 2003; 22: 5293-5303Crossref PubMed Scopus (345) Google Scholar). Therefore, XPA must bind the 3′ junction of the NER bubble (Figure 1B). As the XPG nuclease binds primarily to the dsDNA beyond the 3′ junction (Hohl et al., 2003Hohl M. Thorel F. Clarkson S.G. Schärer O.D. J. Biol. Chem. 2003; 278: 19500-19508Crossref PubMed Scopus (56) Google Scholar), there would be no direct competition between XPA and XPG for binding to the substrate. Although the human NER proteins have proven extremely difficult to characterize structurally, they are slowly revealing their secrets. The model of XPF-ERCC1 bound to the 5′ bubble junction represents the culmination of multiple structural studies and provides a fresh perspective on a critical complex in the NER process. The proposed model also highlights the critical requirement to study full-length proteins and multi-protein complexes to understand how the evolving architecture of the NER machine, and the resulting structural changes induced in the DNA substrate, drive the progression of biochemical steps required for repair. Research on NER in our laboratory is supported by the National Institutes of Health (Grants R01 ES1065561, P01 CA92584, P30 CA68485, and P30 ES00267) and a postdoctoral fellowship from the American Cancer Society (Grant PF-11-271-01-DMC). We are grateful to Rachel C. Wright for preparation of the figure. The Structure of the XPF-ssDNA Complex Underscores the Distinct Roles of the XPF and ERCC1 Helix- Hairpin-Helix Domains in ss/ds DNA RecognitionDas et al.StructureApril 04, 2012In BriefHuman XPF/ERCC1 is a structure-specific DNA endonuclease that nicks the damaged DNA strand at the 5′ end during nucleotide excision repair. We determined the structure of the complex of the C-terminal domain of XPF with 10 nt ssDNA. A positively charged region within the second helix of the first HhH motif contacts the ssDNA phosphate backbone. One guanine base is flipped out of register and positioned in a pocket contacting residues from both HhH motifs of XPF. Comparison to other HhH-containing proteins indicates a one-residue deletion in the second HhH motif of XPF that has altered the hairpin conformation, thereby permitting ssDNA interactions. Full-Text PDF Open Archive" @default.
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• W2169385246 date "2012-04-01" @default.
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• W2169385246 title "XPF-ERCC1: On the Bubble" @default.
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