Ordered Conformational Changes in Damaged DNA Induced by Nucleotide Excision Repair Factors

In response to genotoxic attacks, cells activate sophisticated DNA repair pathways such as nucleotide excision repair (NER), which consists of damage removal via dual incision and DNA resynthesis. Using permanganate footprinting as well as highly purified factors, we show that NER is a dynamic process that takes place in a number of successive steps during which the DNA is remodeled around the lesion in response to the various NER factors. XPC/HR23B first recognizes the damaged structure and initiates the opening of the helix from position -3 to +6. TFIIH is then recruited and, in the presence of ATP, extends the opening from position -6 to +6; it also displaces XPC downstream from the lesion, thereby providing the topological structure for recruiting XPA and RPA, which will enlarge the opening. Once targeted by XPG, the damaged DNA is further melted from position -19 to +8. XPG and XPF/ERCC1 endonucleases then cut the damaged DNA at the limit of the opened structure that was previously “labeled” by the positioning of XPC/HR23B and TFIIH. In response to genotoxic attacks, cells activate sophisticated DNA repair pathways such as nucleotide excision repair (NER), which consists of damage removal via dual incision and DNA resynthesis. Using permanganate footprinting as well as highly purified factors, we show that NER is a dynamic process that takes place in a number of successive steps during which the DNA is remodeled around the lesion in response to the various NER factors. XPC/HR23B first recognizes the damaged structure and initiates the opening of the helix from position -3 to +6. TFIIH is then recruited and, in the presence of ATP, extends the opening from position -6 to +6; it also displaces XPC downstream from the lesion, thereby providing the topological structure for recruiting XPA and RPA, which will enlarge the opening. Once targeted by XPG, the damaged DNA is further melted from position -19 to +8. XPG and XPF/ERCC1 endonucleases then cut the damaged DNA at the limit of the opened structure that was previously “labeled” by the positioning of XPC/HR23B and TFIIH. To counteract the detrimental effect of genotoxic attacks, cells activate sophisticated and specific DNA repair pathways. Damage induced by UV radiation, environmental agents, and anticancer drugs are removed by two distinct nucleotide excision repair (NER) 1The abbreviations used are: NER, nucleotide excision repair; ROS, reconstituted opening system; RPA, replication protein A; XPA/C/F/G, xeroderma pigmentosum group A, C, F, or G. subpathways, namely global genome repair (GGR), which eliminates lesions from the entire genome, and transcription-coupled repair (TCR), a specialized pathway that repairs damages on a transcribed strand of active genes (1Bohr V.A. Smith C.A. Okumoto D.S. Hanawalt P.C. Cell. 1985; 40: 359-369Google Scholar, 2Hoeijmakers J.H. Nature. 2001; 411: 366-374Google Scholar, 3Mellon I. Spivak G. Hanawalt P.C. Cell. 1987; 51: 241-249Google Scholar). Human NER involves the ordered action of factors in dual incision and DNA repair resynthesis steps (4De Laat W.L. Jaspers N.G. Hoeijmakers J.H. Genes Dev. 1999; 13: 768-785Google Scholar). Any mutation that affects either the enzymatic activity or the ordered assembly of the dual incision complex leads to genetic disorders such as xeroderma pigmentosum, trichothiodystrophy, or Cockayne syndrome (5Bootsma D. Kraemer K.H. Cleaver J.E. Hoeijmakers J.H.J. Vogelstein B. Kinzler K.W. The Genetic Basis of Human Cancer. McGraw-Hill Inc., New York1998: 245-274Google Scholar, 6Lehmann A.R. Genes Dev. 2001; 15: 15-23Google Scholar). In global genome repair, the dual incision is a multistep process that results from the coordinated action of XPC/HR23B, TFIIH, XPA, RPA, XPG, and XPF/ERCC1, resulting in the removal of the damaged oligonucleotide (4De Laat W.L. Jaspers N.G. Hoeijmakers J.H. Genes Dev. 1999; 13: 768-785Google Scholar, 7Araujo S.J. Tirode F. Coin F. Pospiech H. Syvaoja J.E. Stucki M. Hubscher U. Egly J.M. Wood R.D. Genes Dev. 2000; 14: 349-359Google Scholar, 8Sancar A. Annu. Rev. Biochem. 1996; 65: 43-81Google Scholar). After being recognized by the XPC/HR23B complex, the damaged DNA structure is targeted by TFIIH, which recruits the other factors upon the addition of ATP (9Sugasawa K. Ng J. Masutani C. Iwai S. van der Spek P. Eker A. Hanaoka F. Bootsma D. Hoeijmakers J. Mol. Cell. 1998; 2: 223-232Google Scholar, 10Volker M. Mone M.J. Karmakar P. van Hoffen A. Schul W. Vermeulen W. Hoeijmakers J.H. van Driel R. van Zeeland A.A. Mullenders L.H. Mol. Cell. 2001; 8: 213-224Google Scholar, 11Riedl T. Hanaoka F. Egly J.M. EMBO J. 2003; 22: 5293-5303Google Scholar). The unwound DNA is then incised by the two endonucleases XPG and XPF/ERCC1 on the 3′ and 5′ side of the lesion, respectively (12O'Donnovan A. Davies A.A. Moggs J.G. West S.C. Wood R.D. Nature. 1994; 371: 432-435Google Scholar, 13Evans E. Fellows J. Coffer A. Wood R.D. EMBO J. 1997; 16: 625-638Google Scholar, 14de Laat W.L. Appeldoorn E. Jaspers N.G.J. Hoeijmakers J.H.J. J. Biol. Chem. 1998; 273: 7835-7842Google Scholar, 15Sijbers A.M. de Laat W.L. Ariza R.R. Biggerstaff M. Wei Y.F. Moggs J.G. Carter K.C. Shell B.K. Evans E. de Jong M.C. Rademakers S. de Rooij J. Jaspers N.G. Hoeijmakers J.H. Wood R.D. Cell. 1996; 86: 811-822Google Scholar), leaving a gap structure that is filled up by the DNA polymerase ϵ or δ and the accompanying factors PCNA, RF-C, RPA, and DNA ligase I (16Shivji M.K.K. Podust V.N. Hubsher U. Wood R.D. Biochemistry. 1995; 34: 5011-5017Google Scholar). Whether or not the NER reaction occurs by sequential arrival of the various factors or by a pre-assembled complex referred to as the repairosome or the holoenzyme is still under debate (17Svejstrup J.Q. Wang Z. Feaver W.J. Wu X. Bushnell D.A. Donahue T.F. Friedberg E.C. Kornberg R.D. Cell. 1995; 80: 21-28Google Scholar, 18Houtsmuller A.B. Rademakers S. Nigg A.L. Hoogstraten D. Hoeijmakers J.H. Vermeulen W. Science. 1999; 284: 958-961Google Scholar, 19Maldonado E. Shiekhattar R. Sheldon M. Cho H. Drapkin R. Rickert P. Lees E. Anderson C.W. Linn S. Reinberg D. Nature. 1996; 381: 86-89Google Scholar). Although the hypothesis of the sequential assembly, which has gained a lot of support from recent biological studies, seems to be more accepted, the order of assembly of the NER factors on the damaged DNA and their contribution to the DNA remodeling to allow the repair are not fully understood (10Volker M. Mone M.J. Karmakar P. van Hoffen A. Schul W. Vermeulen W. Hoeijmakers J.H. van Driel R. van Zeeland A.A. Mullenders L.H. Mol. Cell. 2001; 8: 213-224Google Scholar, 20Araujo S.J. Nigg E.A. Wood R.D. Mol. Cell. Biol. 2001; 21: 2281-2291Google Scholar, 21Reardon J.T. Sancar A. Mol. Cell. Biol. 2002; 22: 5938-5945Google Scholar). As an example, to further learn about the role of TFIIH and its XPB and XPD helicases in NER, it is necessary to determine how it associates with the damaged DNA and recruits the additional factors such as XPA and RPA to promote the formation of an open intermediate essential for the dual incision by XPG and XPF endonucleases. In the present study, we have focused our attention on the damaged DNA itself, trying to understand how the various NER factors target it and remodel it to finally allow its opening and dual incision. Thus, we have set up a permanganate footprinting assay for analyzing the formation of single-stranded DNA regions induced by the NER factors and, furthermore, a site-specific protein-DNA assay for the of NER factors around the Using purified factors, we to determine the role of in the DNA at the various of the NER damaged DNA DNA of the open and oligonucleotide incision. and XPA, and XPC from a and in the was to XPA and The resulting with DNA in and by a The RPA and XPG J. Biol. Chem. 1994; Scholar, A. D. Wood R.D. J. Biol. Chem. 1994; Scholar). of the complex was as previously Laat W.L. Appeldoorn E. Jaspers N.G.J. Hoeijmakers J.H.J. J. Biol. Chem. 1998; 273: 7835-7842Google Scholar). cells with and in and and for at The was for as for and and to a and the was then to a the protein at and further for with of the in the presence of After sequential with and and, and the complex was in and and purified to A.M. de Laat W.L. Ariza R.R. Biggerstaff M. Wei Y.F. Moggs J.G. Carter K.C. Shell B.K. Evans E. de Jong M.C. Rademakers S. de Rooij J. Jaspers N.G. Hoeijmakers J.H. Wood R.D. Cell. 1996; 86: 811-822Google Scholar). The XPC/HR23B complex or its and and purified from cells K. Masutani C. A. T. van der Spek Bootsma D. Hoeijmakers J.H. Hanaoka F. Mol. Cell. Biol. 1996; 16: Scholar). The RPA complex was in and purified J. Biol. Chem. 1994; Scholar). XPG was in cells and purified as A. D. Wood R.D. J. Biol. Chem. 1994; Scholar). of the NER factors and XPA was on a in and with XPA was then in for and and for at with of After the the was with and XPA was in and with The and C. TFIIH was purified from cells M. J.M. P. Egly J.M. J. Biol. Chem. Scholar). lesion P. K. Coin F. J. S. B. Egly J.M. Mol. Cell. 2002; Scholar), was used for dual incision S.J. Tirode F. Coin F. Pospiech H. Syvaoja J.E. Stucki M. Hubscher U. Egly J.M. Wood R.D. Genes Dev. 2000; 14: 349-359Google in a reaction XPC/HR23B XPA RPA XPG XPF/ERCC1 and TFIIH in the presence of of at of the was and the further for The was on with the oligonucleotide and the addition of by P. K. Coin F. J. S. B. Egly J.M. Mol. Cell. 2002; Scholar). damaged strand was upon of the P. K. Coin F. J. S. B. Egly J.M. Mol. Cell. 2002; and at the in a the being at from the the was by and then by The resulting in which the lesion is from the 3′ was purified by the and in a J. E. T. Scholar). in and the and, ATP, XPC/HR23B XPA RPA XPG XPF/ERCC1 and TFIIH After at for of was and was to for at by of for in After and in of a and and at for and in of and in strand or in strand In of the nucleotide complex assembly, and of the as previously M. Coin F. J.M. Egly J.M. B. Mol. Cell. Biol. 2000; Scholar, F. B. Mol. Biol. 2001; Scholar). the of the that place two on the 3′ side of the and we used of various to allow at the are the to the of the that place two on the 5′ side of the and we used a oligonucleotide and an additional 5′ oligonucleotide for the of with DNA polymerase and as previously M. Coin F. J.M. Egly J.M. B. Mol. Cell. Biol. 2000; Scholar, F. B. Mol. Biol. 2001; Scholar). After of the with either XPC/HR23B or XPC/HR23B and TFIIH in the presence of ATP In of DNA in the NER the DNA opening of the NER we set up a permanganate assay that the of single-stranded DNA around the DNA by in upon In such an the in single-stranded DNA in and the be to strand by J. Biol. Chem. 1995; Scholar). In of in DNA structure upon protein are assay to damaged DNA a and the in footprinting upon with the highly purified factors XPC/HR23B, XPA, RPA, TFIIH, XPG, and XPF/ERCC1 S.J. Tirode F. Coin F. Pospiech H. Syvaoja J.E. Stucki M. Hubscher U. Egly J.M. Wood R.D. Genes Dev. 2000; 14: 349-359Google Scholar, P. K. Coin F. J. S. B. Egly J.M. Mol. Cell. 2002; Scholar). set of factors is necessary and to the damaged and the of of the factors the dual incision reaction around the open the DNA in the of XPF/ERCC1 and the reconstituted opening a of the of the single-stranded damaged DNA with an of the around the lesion at and and the of at and and as in In the of NER factors, at and from the induced by the damage also the of induced by the permanganate in the strand upon the addition of the factors at and In the of TFIIH and XPC/HR23B, not and of the DNA around the by the NER factors. A, opening around the during NER, as by to is by of or the of the The position of the incision by XPG and XPF/ERCC1 endonucleases are by The of the the with XPC/HR23B, either or in the presence of TFIIH and ATP for for a the of XPC in the presence of TFIIH and the various steps to the removal of the damaged is by an in the remodeling of damaged DNA that is opened by the repair In the of TFIIH, XPC the damaged DNA from to the at being the In the presence of TFIIH, XPC to and to not to on the 3′ of the The fully open complex to is used as a for incision by XPF/ERCC1 and XPG as by XPC DNA and the NER the of to target the damaged XPC/HR23B in the footprinting at and and C, are also an DNA from about to not further of the helix in the other factors with the DNA The addition of XPF/ERCC1 to the damaged DNA a at position as well as at and on side of the lesion, respectively the of which will be that the of the is the is in the of NER factors from to for example, have the in the of of the TFIIH, XPA, RPA, and XPG factors was to to helix opening in the of in the footprinting was the of factors under upon we a at and in the presence of XPA and TFIIH not the complex was to for damaged DNA S. Coin F. M. K. Egly J. Biol. 1997; Scholar). the results are fully with an role for the XPC/HR23B complex in of the damage and of the other NER factors by other (9Sugasawa K. Ng J. Masutani C. Iwai S. van der Spek P. Eker A. Hanaoka F. Bootsma D. Hoeijmakers J. Mol. Cell. 1998; 2: 223-232Google Scholar, 10Volker M. Mone M.J. Karmakar P. van Hoffen A. Schul W. Vermeulen W. Hoeijmakers J.H. van Driel R. van Zeeland A.A. Mullenders L.H. Mol. Cell. 2001; 8: 213-224Google Scholar). also the contribution of of the XPC/HR23B complex K. Masutani C. A. T. van der Spek Bootsma D. Hoeijmakers J.H. Hanaoka F. Mol. Cell. Biol. 1996; 16: Scholar, C. K. J. T. M. T. K. K. van der Spek Bootsma D. Hoeijmakers J.H.J. Hanaoka F. EMBO J. 1994; 13: Scholar). The addition of either XPC or to the damaged DNA permanganate footprinting as by the opening at and the XPC/HR23B complex is the addition of XPC/HR23B, the is with either XPC or is with and Although either XPC or target the damaged DNA and the addition of XPA, RPA, XPG, and TFIIH to not promote the opening that not allow the of the factors their XPA, RPA, XPG, and TFIIH are with either or in with are at and and and also the essential role of XPC in recruiting other NER factors. In with the the addition of to XPA, RPA, XPG, TFIIH, or XPF/ERCC1 not allow the removal of the damaged oligonucleotide XPC is TFIIH to the and DNA that XPC has an role in open complex we the contribution of RPA, XPA, XPG, and TFIIH to DNA opening by the damaged DNA with the in which NER was The of TFIIH in the of the of the footprinting induced by XPC/HR23B with and the of RPA or XPG not the footprinting and in the of XPA, the footprinting at and as well as at the damage is Once XPC/HR23B and TFIIH are to the damaged additional NER factors are to the footprinting on the 5′ on the 3′ side are NER factors the role of ATP, which is for the activity of the XPB and XPD helicases of TFIIH R. S. Vermeulen W. Hoeijmakers J.H.J. P. Egly J.M. Science. Scholar, S.J. U. Vermeulen W. Coin F. Egly J.M. Hoeijmakers J.H. Wood R.D. G. J. Biol. Chem. 2000; Scholar, F. E. A. Egly J.M. 1999; in the footprinting of the damaged DNA around the lesion E. Moggs J.G. Egly Wood R.D. EMBO J. 1997; 16: Scholar). first that ATP not the XPC/HR23B footprinting of the damaged DNA and The addition of TFIIH in the of ATP not allow of the DNA and In the presence of ATP, TFIIH the DNA to the footprinting in which permanganate are at and and the damage The footprinting induced by XPC/HR23B and TFIIH is in the presence of XPA at and and additional at and The addition of either RPA or XPG in the of XPA the opening around the damage and at and of the factors are the addition of ATP is for dual incision and The addition of RPA to a reaction TFIIH, and XPA not the footprinting of the damaged strand and the addition of XPG the in the presence of and are and the is we a at and and Although RPA was to damaged DNA U. T. G. G. 1999; Scholar, Biochemistry. 2002; Scholar), under our it not the single-stranded structure induced by XPC and TFIIH and RPA, either or in not the permanganate footprinting of the damaged and the DNA strand and The for the addition of NER factors, TFIIH, XPA, RPA, and XPG, we an and footprinting In such a and are and In the presence of XPF/ERCC1 we a of the at and the lesion at and as well as the of other at and and also and of our we the additional induced by XPG and XPF/ERCC1 either or in the of either an of the DNA opening or in the damaged the of either XPG or XPF/ERCC1 to the DNA on side of the lesion was in under the that the incision reaction set of was XPG is to the intermediate complex XPC/HR23B, TFIIH, XPA, and RPA, we cut at position and to the intermediate complex, XPF/ERCC1 not the damaged DNA in the presence of the NER factors incision at position -3 that results from an positioning of XPF/ERCC1 on the intermediate complex in the of XPG also in such a XPG and XPF are for example, and the of and at the addition of XPF/ERCC1, with XPG, the footprinting of the 3′ incision at and with a of the on the 5′ side of the lesion and the of at and To by and resulting from the XPG XPF/ERCC1 DNA on a and of incision reaction in the of permanganate the addition of XPF/ERCC1, we the formation of on of the opened DNA at and and and show that XPG and XPF in and that the occurs at the limit of the opened DNA the XPG activity was by either the presence of XPF or the enzymatic activity of and two XPF in activity and the dual incision reaction not DNA the activity of XPG to cut damaged DNA J.H. EMBO J. 2002; 21: Scholar). in the presence of and we a 5′ footprinting to the in the of XPF/ERCC1 we that the presence of the XPF the at and with the being an as in the incision assay for it is to that the other and the presence of an active more the in the of the damaged of XPC and XPB around the have used site-specific protein-DNA to determine the of XPC/HR23B and TFIIH the two factors that the formation of the complex and around the the nucleotide at specific around the damage The DNA repair complex either XPC/HR23B or XPC/HR23B and TFIIH was with the various in the presence of ATP and further the of be to the at a of from the DNA J. B. Mol. Biol. 2001; Scholar, B. EMBO J. Scholar, C. B. Mol. Cell. Biol. Scholar). The then with to DNA and the by To the of the of the in with the which not in the formation of protein-DNA not was specific its was in the damaged as with the The of the DNA repair factors XPC/HR23B and TFIIH with the damaged DNA is that the of the factors and polymerase with DNA M. Coin F. J.M. Egly J.M. B. Mol. Cell. Biol. 2000; Scholar), which the of the in XPC/HR23B was used in the we of XPC at the TFIIH and ATP to XPC/HR23B, we of XPB at at position is as well as of XPC at the two of the damage position and the of the XPC and XPB in our in the presence of XPC/HR23B and TFIIH. the of XPB is that of XPC at factors with at XPB to and XPC not to and in the presence of TFIIH. results that XPC DNA around the lesion in the of TFIIH is from the 3′ side of the lesion TFIIH associates with the complex, that the of TFIIH a of XPC in the to our results also that XPB is the TFIIH that in with the open results that NER is a dynamic process that takes place in a number of successive steps from DNA damage to its (10Volker M. Mone M.J. Karmakar P. van Hoffen A. Schul W. Vermeulen W. Hoeijmakers J.H. van Driel R. van Zeeland A.A. Mullenders L.H. Mol. Cell. 2001; 8: 213-224Google Scholar, E. Moggs J.G. Egly Wood R.D. EMBO J. 1997; 16: Scholar, A. D. Evans E. P. Wood R.D. J. Biol. Chem. 1999; Scholar, D. M. D.S. Sancar A. J. Biol. Chem. 1997; Scholar), during which process the repair factors the of the damaged DNA have that a DNA is by M. Scholar, J.H. S.J. Biochemistry. 40: Scholar, van J. Biochem. 1994; Scholar). permanganate footprinting further that the DNA is melted from -3 and around the E. Fellows J. Coffer A. Wood R.D. EMBO J. 1997; 16: 625-638Google Scholar, A. D. Evans E. P. Wood R.D. J. Biol. Chem. 1999; Scholar). DNA is recognized and by the XPC/HR23B that XPC the damaged DNA a from about to the DNA opening from -3 to and the DNA to the to and downstream to of the of XPC/HR23B then the of TFIIH in an present and 11Riedl T. Hanaoka F. Egly J.M. EMBO J. 2003; 22: 5293-5303Google Scholar). In the presence of ATP, TFIIH further the damaged DNA from -6 to +6. is that the XPB of TFIIH is the that more the damaged As by our the of TFIIH with the complex displaces which not the DNA downstream of the lesion in the presence of TFIIH. is the of ATP addition that XPB and XPD helicases to the damaged resulting in an intermediate complex to the other NER factors. Although XPC and a to the damaged not remodel the damaged DNA to the other NER factors, its role in the in dual incision K. Masutani C. A. T. van der Spek Bootsma D. Hoeijmakers J.H. Hanaoka F. Mol. Cell. Biol. 1996; 16: Scholar, K. Ng J.M. Masutani C. T. A. van der Spek Eker Rademakers S. C. A. Wood R.D. Hanaoka F. Bootsma D. Hoeijmakers J.H. Mol. Cell. Biol. 1997; Scholar, D. Wood R.D. J. Mol. Biol. 2000; Scholar). that the addition of TFIIH to that in the presence of ATP, not support of the damaged XPC recruits TFIIH in the of M. Masutani C. T. K. Hanaoka F. J. Biol. Chem. 2000; Scholar). The of the DNA around the damage -6 and is by XPA, which the of the by XPC and TFIIH The present a contribution of XPA in further the DNA opening by XPC and TFIIH. The of RPA on the DNA activity of TFIIH and the opening of the damaged DNA to J.T. Sancar A. Mol. Cell. Biol. 2002; 22: 5938-5945Google Scholar, Wood R.D. Biochemistry. Scholar, M. Sancar A. J. Biol. Chem. 1999; Scholar, Biochemistry. 1998; Scholar, M. T. R. Hubscher U. J. H. EMBO J. 2001; Scholar), under our XPA RPA the complex not was to the opening of the damaged DNA and the formation of the dual incision Although RPA was to be on the 5′ side of the damaged DNA U. T. G. G. 1999; to single-stranded DNA from the present to the of RPA the damaged DNA intermediate complex that the presence of RPA, with TFIIH, and XPA, is for the dual incision and DNA resynthesis steps S.J. Tirode F. Coin F. Pospiech H. Syvaoja J.E. Stucki M. Hubscher U. Egly J.M. Wood R.D. Genes Dev. 2000; 14: 349-359Google Scholar, A. Biggerstaff M. M.K.K. Podust V.N. M. U. Egly J.M. Wood R.D. Cell. 1995; 80: Scholar, D. T. D.S. J.T. Sancar A. J. Biol. Chem. 1995; T. Hanaoka F. Egly J.M. EMBO J. 2003; 22: 5293-5303Google Scholar). RPA position XPG and XPF it is also in the of factors such as and to the DNA resynthesis Laat W.L. Appeldoorn E. K. E. Jaspers N.G. Hoeijmakers J.H. Genes Dev. 1998; A. Z. J. M. EMBO J. 1999; Scholar). The complex that results from the ordered addition of XPC/HR23B, TFIIH, XPA, and RPA is then to be targeted by XPG and XPF/ERCC1 endonucleases that will the damaged XPG first and the other XPG the a 5′ 3′ structure A. Davies A.A. Moggs J.G. West S.C. Wood R.D. Nature. 1994; 371: 432-435Google Scholar, 13Evans E. Fellows J. Coffer A. Wood R.D. EMBO J. 1997; 16: 625-638Google Scholar, and M. F. J. Biol. Chem. 2003; Scholar, and our that XPG is to and the damaged that it is with the NER factors and a DNA with a at and a 5′ single-stranded XPG will cut the DNA at position the addition of XPF/ERCC1 XPG incision to additional at and a in results from the of factors and the of T. Hanaoka F. Egly J.M. EMBO J. 2003; 22: 5293-5303Google Scholar). XPF/ERCC1, either or in with the NER factors of the intermediate complex, the damaged DNA as well as 14de Laat W.L. Appeldoorn E. Jaspers N.G.J. Hoeijmakers J.H.J. J. Biol. Chem. 1998; 273: 7835-7842Google and J.H. EMBO J. 2002; 21: Scholar, and the present The of XPF in on the 5′ side is XPG has the XPF and XPG in to the damaged Whether or not the of additional not factors to allow a and specific cut The of XPG and XPF/ERCC1 has previously to the of XPC/HR23B and TFIIH, respectively T. Hanaoka F. Egly J.M. EMBO J. 2003; 22: 5293-5303Google Scholar). we show that XPG and XPF endonucleases target and the damaged DNA at by XPC and TFIIH. is to how the various factors with the damaged it is recognized by unwound by XPB and XPD of its open structure is then by XPA, and it is by XPG and in the genes factors xeroderma pigmentosum, which is in with and in the RPA, and genes have not with NER the of factors in DNA is necessary in of the genes for the dual incision in NER has to be further not to a also to the role of of in DNA T. and S. for and of the and R. J. H. J. and S. for providing and are to M. and A. for I. and J. for the of and B. and S. for their in and the

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