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• W2057243520 abstract "Transcription factor IIH (TFIIH) is involved both in transcription initiation by RNA polymerase II and in nucleotide excision-repair. Nucleotide excision-repair occurs at higher rates in transcriptionally active regions of the genome. Genetic studies indicate that this transcription-coupled repair is dependent on the Cockayne syndrome group A and B proteins, as well as TFIIH subunits. Previous work indicated that Cockayne syndrome group B interacts with RNA polymerase II molecules engaged in ternary complexes containing DNA and RNA. Evidence presented here indicates that this complex can interact with a factor containing the TFIIH core subunits p62 and xeroderma pigmentosum subunit B/excision repair cross-complementing 3. The targeting of TFIIH or a TFIIH-like repair factor to transcriptionally active DNA indicates a potential mechanism for transcription-coupled repair in human cells. Transcription factor IIH (TFIIH) is involved both in transcription initiation by RNA polymerase II and in nucleotide excision-repair. Nucleotide excision-repair occurs at higher rates in transcriptionally active regions of the genome. Genetic studies indicate that this transcription-coupled repair is dependent on the Cockayne syndrome group A and B proteins, as well as TFIIH subunits. Previous work indicated that Cockayne syndrome group B interacts with RNA polymerase II molecules engaged in ternary complexes containing DNA and RNA. Evidence presented here indicates that this complex can interact with a factor containing the TFIIH core subunits p62 and xeroderma pigmentosum subunit B/excision repair cross-complementing 3. The targeting of TFIIH or a TFIIH-like repair factor to transcriptionally active DNA indicates a potential mechanism for transcription-coupled repair in human cells. transcription factor excision repair cross-complementing carboxyl-terminal domain nucleotide excision-repair xeroderma pigmentosum Cockayne's syndrome hemagglutinin transcription-coupled repair. TFIIH1 is a complex factor capable of multiple functions (for review, see Hoeijmakerset al. (1Hoeijmakers J.H.J. Egly J.-M. Vermeulen W. Curr. Opin. Genet. Dev. 1996; 6: 26-33Crossref PubMed Scopus (155) Google Scholar)). It contains approximately nine subunits, although considerable compositional variability has been reported (2Svejstrup J.Q. Wang Z. Feaver W.J. Wu X. Bushnell D.A. Donahue T.F. Friedberg E.C. Kornberg R.D. Cell. 1995; 80: 21-28Abstract Full Text PDF PubMed Scopus (238) Google Scholar, 3Garcı́a-Martı́nez L.F. Mavankal G. Neveu J.M. Lane W.S. Ivanov D. Gaynor R.B. EMBO J. 1997; 16: 2836-2850Crossref PubMed Scopus (116) Google Scholar, 4Reardon J.T. Ge H. Gibbs E. Sancar A. Hurwitz J. Pan Z.Q. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 6482-6487Crossref PubMed Scopus (99) Google Scholar, 5Serizawa H. Mäkel T.P. Conaway J.W. Conaway R.C. Weinberg R.A. Young R.A. Nature. 1995; 374: 280-282Crossref PubMed Scopus (308) Google Scholar). TFIIH contains multiple enzymatic activities, including two distinct DNA helicase activities encoded by the xeroderma pigmentosum (XP) B/excision repair cross-complementing (ERCC) 3 and XPD/ERCC2 subunits (6Schaeffer L. Roy R. Humbert S. Moncollin V. Vermeulen W. Hoeijmakers J.H. Chambon P. Egly J.M. Science. 1993; 260: 58-63Crossref PubMed Scopus (664) Google Scholar, 7Schaeffer L. Moncollin V. Roy R. Staub A. Mezzina M. Sarasin A. Weeda G. Hoeijmakers J.H. Egly J.M. EMBO J. 1994; 13: 2388-2392Crossref PubMed Scopus (333) Google Scholar), and a kinase activity capable of phosphorylating the pol II large subunit carboxyl-terminal domain (CTD) (5Serizawa H. Mäkel T.P. Conaway J.W. Conaway R.C. Weinberg R.A. Young R.A. Nature. 1995; 374: 280-282Crossref PubMed Scopus (308) Google Scholar, 8Lu H. Zawel L. Fisher L. Egly J.M. Reinberg D. Nature. 1992; 358: 641-645Crossref PubMed Scopus (329) Google Scholar). In addition to XPD and XPB, several other TFIIH subunits are important NER factors (9Humbert S. van Vuuren H. Lutz Y. Hoeijmakers J.H. Egly J.M. Moncollin V. EMBO J. 1994; 13: 2393-2398Crossref PubMed Scopus (100) Google Scholar, 10Wang Z. Buratowski S. Svejstrup J.Q. Feaver W.J. Wu X. Kornberg R.D. Donahue T.F. Friedberg E.C. Mol. Cell. Biol. 1995; 15: 2288-2293Crossref PubMed Scopus (75) Google Scholar, 11Drapkin R. Reardon J.T. Ansari A. Huang J.C. Zawel L. Ahn K. Sancar A. Reinberg D. Nature. 1994; 368: 769-772Crossref PubMed Scopus (407) Google Scholar, 12Marinoni J.C. Roy R. Vermeulen W. Miniou P. Lutz Y. Weeda G. Seroz T. Gomez D.M. Hoeijmakers J.H. Egly J.M. EMBO J. 1997; 16: 1093-1102Crossref PubMed Scopus (60) Google Scholar).Under most conditions, TFIIH is required for pol II transcription initiation. The need for TFIIH correlates with the well documented pol II requirement for the energetic β-γ phosphoanhydride bond of ATP (13Bunick D. Zandomeni R. Ackerman S. Weinmann R. Cell. 1982; 29: 877-886Abstract Full Text PDF PubMed Scopus (107) Google Scholar, 14Sawadogo M. Roeder R.G. J. Biol. Chem. 1984; 259: 5321-5326Abstract Full Text PDF PubMed Google Scholar). Negative supercoiling allows some promoters to initiate transcription without TFIIH in vitro (15Parvin J.D. Sharp P.A. Cell. 1993; 73: 533-540Abstract Full Text PDF PubMed Scopus (307) Google Scholar), and concurrently circumvents the energetic requirement for ATP (16Timmers H.T. EMBO J. 1994; 13: 391-399Crossref PubMed Scopus (90) Google Scholar). Templates bearing heteroduplex start sites also eliminate the requirement both for TFIIH and for hydrolysis of the ATP β-γ phosphoanhydride bond (17Tantin D. Carey M. J. Biol. Chem. 1994; 269: 17397-17400Abstract Full Text PDF PubMed Google Scholar, 18Pan G. Greenblatt J. J. Biol. Chem. 1994; 269: 30101-30104Abstract Full Text PDF PubMed Google Scholar, 19Holstege F.C. Tantin D. Carey M. van der Vliet P.C. Timmers H.T. EMBO J. 1995; 14: 810-819Crossref PubMed Scopus (130) Google Scholar), suggesting that during pol II initiation, TFIIH uses the energy of ATP hydrolysis to promote local DNA unwinding at the transcription initiation site. This melted DNA intermediate is termed an “open complex.” An open complex is also formed during NER in a manner that is dependent on the TFIIH helicases and ATP (20Evans E. Fellows J. Coffer A. Wood R.D. EMBO J. 1997; 16: 625-638Crossref PubMed Scopus (204) Google Scholar, 21Evans E. Moggs J.G. Hwang J.R. Egly J.M. Wood R.D. EMBO J. 1997; 16: 6559-6573Crossref PubMed Scopus (398) Google Scholar). The NER open complex appears to serve as an substrate for the site-specific endonucleases XPG and XPF. TFIIH is also implicated in post-initiation events, such as promoter escape and pol II elongation (22Dvir A. Conaway R.C. Conaway J.W. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 9006-9010Crossref PubMed Scopus (113) Google Scholar).Recent studies have suggested that TFIIH exists in multiple forms (23Roy R. Adamczewski J.P. Seroz T. Vermeulen W. Tassan J.P. Schaeffer L. Nigg E.A. Hoeijmakers J.H. Egly J.M. Cell. 1994; 79: 1093-1101Abstract Full Text PDF PubMed Scopus (387) Google Scholar,24Feaver W.J. Svejstrup J.Q. Henry N.L. Kornberg R.D. Cell. 1994; 79: 1103-1109Abstract Full Text PDF PubMed Scopus (359) Google Scholar). In a transcriptionally active form, a set of common “core” subunits, consisting of XPB/ERCC3 (yeast SSL2), XPD/ERCC2 (RAD3), p62 (TFB1), p52 (TFB2), p44 (SSL1), and p34 (TFB4) (reviewed in Refs. 25Sancar A. Annu. Rev. Biochem. 1996; 65: 43-81Crossref PubMed Scopus (960) Google Scholarand 26Svejstrup J.Q. Vichi P. Egly J.-M. Trends. Biol. Sci. 1996; 249: 346-350Crossref Scopus (211) Google Scholar)), associate with a cyclin-Cdk complex that contains Cdk7/MO15 (yeast KIN28), cyclin H (CCL1), and MAT1 (TFB3). This kinase complex was previously equated with an activity, Cdk-activating kinase (known as CAK), that could phosphorylate and activate other Cdk molecules. Although evidence indicates that this complex may not be the physiologically relevant form of Cdk-activating kinase in yeast (27Cismowski M.J. Laff G.M. Solomon M.J. Reed S.I. Mol. Cell. Biol. 1995; 15: 2983-2992Crossref PubMed Scopus (189) Google Scholar), the Cdk7 complex may nevertheless fulfill this role in metazoans (28Larochelle S. Pandur J. Fisher R.P. Salz H.K. Suter B. Genes Dev. 1998; 12: 370-381Crossref PubMed Scopus (145) Google Scholar). Another form of TFIIH is associated with other NER proteins and has been termed the “repairosome” (2Svejstrup J.Q. Wang Z. Feaver W.J. Wu X. Bushnell D.A. Donahue T.F. Friedberg E.C. Kornberg R.D. Cell. 1995; 80: 21-28Abstract Full Text PDF PubMed Scopus (238) Google Scholar, 29Bardwell A.J. Bardwell L. Iyer N. Svejstrup J.Q. Feaver W.J. Kornberg R.D. Friedberg E.C. Mol. Cell. Biol. 1994; 14: 3569-3576Crossref PubMed Scopus (63) Google Scholar, 30He Z. Ingles C.J. Nucleic Acids Res. 1997; 25: 1136-1141Crossref PubMed Scopus (25) Google Scholar).A number of human disorders stem from defects in TFIIH subunits. For example, mutations in several TFIIH subunits can lead to XP, a condition typified by extreme UV sensitivity, a high incidence of cancer, and defective NER. Specific mutations in the TFIIH subunits XPB and XPD, as well as the TFIIH-associated repair factor XPG, cause XP with manifestations of Cockayne's syndrome (CS), a complex disorder characterized by mental retardation, small stature, neurological defects, and UV sensitivity (reviewed in Lehman (31Lehmann A.R. Trends Biochem. Sci. 1995; 20: 402-405Abstract Full Text PDF PubMed Scopus (136) Google Scholar)). Cells taken from CS patients are sensitive to various DNA-damaging agents, such as UV radiation and the UV-mimetic agentN-acetoxy-2-acetylaminofluorene (32Schmickel R.D. Chu E.H.Y. Trosko J.E. Chang C.C. Pediatrics. 1977; 60: 135-139PubMed Google Scholar, 33van Oosterwijk M.F. Versteeg A. Filon R. van Zeeland A.A. Mullenders L.H. Mol. Cell. Biol. 1996; 16: 4436-4444Crossref PubMed Scopus (87) Google Scholar), and they fail to recover the ability to synthesize RNA after exposure to UV (34Mayne L.V. Lehmann A.R. Cancer Res. 1982; 42: 1473-1478PubMed Google Scholar, 35van Hoffen A. Natarajan A.T. Mayne L.V. van Zeeland A.A. Mullenders L.H.F. Venema J. Nucleic Acids Res. 1993; 21: 5890-5895Crossref PubMed Scopus (256) Google Scholar). CS cells are also defective in TCR, as transcriptionally active genes do not repair transcriptionally active genes at higher rates than the surrounding DNA (35van Hoffen A. Natarajan A.T. Mayne L.V. van Zeeland A.A. Mullenders L.H.F. Venema J. Nucleic Acids Res. 1993; 21: 5890-5895Crossref PubMed Scopus (256) Google Scholar, 36Venema J. Mullenders L.H. Natarajan A.T. van Zeeland A.A. Mayne L.V. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 4707-4711Crossref PubMed Scopus (487) Google Scholar, 37Leadon S.A. Cooper P.K. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 10499-10503Crossref PubMed Scopus (215) Google Scholar). Interestingly, the majority of CS patients do not harbor mutations in TFIIH subunits, but rather in two genes termedCSA and CSB/ERCC6 (38Troelstra C. van Gool A. de Wit J. Vermeulen W. Bootsma D. Hoeijmakers J.H. Cell. 1992; 71: 939-953Abstract Full Text PDF PubMed Scopus (617) Google Scholar, 39Henning K.A. Li L. Iyer N. McDaniel L.D. Reagan M.S. Legerski R. Schultz R.A. Stefanini M. Lehmann A.R. Mayne L.V. Friedberg E.C. Cell. 1995; 82: 555-564Abstract Full Text PDF PubMed Scopus (407) Google Scholar). Speculation has focused on CSA and CSB as eukaryotic transcription-repair coupling factors (1Hoeijmakers J.H.J. Egly J.-M. Vermeulen W. Curr. Opin. Genet. Dev. 1996; 6: 26-33Crossref PubMed Scopus (155) Google Scholar, 25Sancar A. Annu. Rev. Biochem. 1996; 65: 43-81Crossref PubMed Scopus (960) Google Scholar, 40Friedberg E.C. Annu. Rev. Biochem. 1996; 65: 15-42Crossref PubMed Scopus (212) Google Scholar). In vitro evidence indicates that CSA and CSB interact with one another, that CSA interacts with the TFIIH p44 subunit (39Henning K.A. Li L. Iyer N. McDaniel L.D. Reagan M.S. Legerski R. Schultz R.A. Stefanini M. Lehmann A.R. Mayne L.V. Friedberg E.C. Cell. 1995; 82: 555-564Abstract Full Text PDF PubMed Scopus (407) Google Scholar), and that CSB interacts with the NER damage recognition factor XPA (41Selby C.P. Sancar A. J. Biol. Chem. 1997; 272: 1885-1890Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar) and the TFIIH-associated factor XPG (42Iyer N. Reagan M.S. Wu K.J. Canagarajah B. Friedberg E.C. Biochemistry. 1996; 35: 2157-2167Crossref PubMed Scopus (167) Google Scholar).TFIIH is itself an important repair protein, as both the yeast and mammalian factors were shown to complement NER-defective cell extracts (11Drapkin R. Reardon J.T. Ansari A. Huang J.C. Zawel L. Ahn K. Sancar A. Reinberg D. Nature. 1994; 368: 769-772Crossref PubMed Scopus (407) Google Scholar, 43Wang Z. Svejstrup J.Q. Feaver W.J. Wu X. Kornberg R.D. Friedberg E.C. Nature. 1994; 368: 74-76Crossref PubMed Scopus (137) Google Scholar). The yeast TFIIH was shown to complement a rad3extract, whereas the isolated Rad3 protein could not (43Wang Z. Svejstrup J.Q. Feaver W.J. Wu X. Kornberg R.D. Friedberg E.C. Nature. 1994; 368: 74-76Crossref PubMed Scopus (137) Google Scholar), indicating that Rad3 operated only in the context of the intact complex. These facts indicate that recruitment of TFIIH to sites of DNA damage may be an important step in the repair process. This supposition is substantiated by the finding that TFIIH can be recruited to DNA lesions by the XPA damage recognition protein in the absence of TFIIE, a factor that is important for recruiting TFIIH during formation of a transcription initiation complex (44Park C.-H. Mu D. Reardon J.T. Sancar A. J. Biol. Chem. 1995; 270: 4896-4902Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 45Nocetani S. Coin F. Saijo M. Tanaka K. Egly J.-M. J. Biol. Chem. 1997; 272: 22991-22994Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). Although TFIIH plays a key role in NER, experiments suggest that TFIIH is lost from the pol II complex early in the transcription process and does not associate with the elongating polymerase (46Zawel L. Kumar K.P. Reinberg D. Genes Dev. 1995; 9: 1479-1490Crossref PubMed Scopus (264) Google Scholar). No evidence for re-recruitment of TFIIH to elongating pol II complexes has thus far been presented, and the potential for recruitment of TFIIH in TCR remains unexplored. More specifically, it is not known whether TFIIH recruitment in TCR follows a transcription-like pathway, in which TFIIE would play a role, a repair-like pathway, in which TFIIH is likely recruited by XPA, a combination of both pathways, or a mechanism in which TFIIH is recruited by other proteins.Previous work described an interaction between transcription complexes containing pol II, DNA, RNA, and the purified CSB/ERCC6 protein (47Tantin D. Kansal A. Carey M. Mol. Cell. Biol. 1997; 17: 6803-6814Crossref PubMed Scopus (166) Google Scholar). The complexes that interact with CSB were shown to be engaged in productive transcription. This interaction requires hydrolysis of the ATP β-γ phosphoanhydride bond. In this study, purified recombinant human CSB, an oligo(dC)-tailed template, immunopurified pol II, and partially purified TFIIH are used to explore the potential of the CSB protein to interact simultaneously with transcribing pol II molecules and with TFIIH. The results indicate that a pol II·CSB·DNA·RNA quaternary complex has the ability to recruit TFIIH or a related factor, providing a plausible mechanism for TCR in mammalian cells.DISCUSSIONAlthough pol II does not appear to directly interact with TFIIH in gel mobility-shift assays, the data support a model in which a molecular complex that contains the TFIIH subunits XPB/ERCC3 and p62 can interact with CSB, which can in turn interact with pol II in ternary complexes containing RNA (Figs. 2 and 3 A) and DNA (Fig. 3 B). This model is depicted in Fig. 4 (right). It provides a possible biochemical basis for the phenomenon of facilitated NER in active genes, including the fact that cells derived from patients with mutations in CSB and certain subunits of TFIIH have a defect in this pathway.CSA and CSB are implicated in the facilitated repair of active genes and linked to TFIIH both genetically and biochemically (reviewed in Friedberg (40Friedberg E.C. Annu. Rev. Biochem. 1996; 65: 15-42Crossref PubMed Scopus (212) Google Scholar)). Cells taken from Cockayne's syndrome patients are defective in TCR (35van Hoffen A. Natarajan A.T. Mayne L.V. van Zeeland A.A. Mullenders L.H.F. Venema J. Nucleic Acids Res. 1993; 21: 5890-5895Crossref PubMed Scopus (256) Google Scholar, 36Venema J. Mullenders L.H. Natarajan A.T. van Zeeland A.A. Mayne L.V. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 4707-4711Crossref PubMed Scopus (487) Google Scholar, 37Leadon S.A. Cooper P.K. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 10499-10503Crossref PubMed Scopus (215) Google Scholar). In addition, mutations in the XPB and XPD subunits of TFIIH and the TFIIH-associated repair factor XPG can also lead to symptoms of CS, and CSA and CSB have been shown, respectively, to interact with TFIIH and XPG in vitro. A recent report found that a species of TFIIH containing XPB/ERCC3 could be recruited (either directly or indirectly) from a HeLa nuclear extract by a fragment of the CSB protein (41Selby C.P. Sancar A. J. Biol. Chem. 1997; 272: 1885-1890Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar). Therefore, it seemed reasonable that CSB could recognize DNA damage in active genes indirectly through pol II and recruit TFIIH or a TFIIH-like complex, facilitating DNA repair.The observation that CSA had no effect on its own, and was not absolutely required for the interactions described here may be explained by that fact that CSB, and not CSA, appears to contain important enzymatic activities (41Selby C.P. Sancar A. J. Biol. Chem. 1997; 272: 1885-1890Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 47Tantin D. Kansal A. Carey M. Mol. Cell. Biol. 1997; 17: 6803-6814Crossref PubMed Scopus (166) Google Scholar, 50Guzder S.N. Habraken Y. Sung P. Prakash L. Prakash S. J. Biol. Chem. 1996; 271: 18314-18317Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar), and the finding that WD repeat-containing proteins are frequently regulatory in nature (51Neer E.J. Schmidt C.J. Nambudripad R. Smith T.F. Nature. 1994; 371: 297-300Crossref PubMed Scopus (1284) Google Scholar). TCR of oxidative base damage is only partially defective in CSA mutant cells, but fully defective in CSB and XPG/CS cells (37Leadon S.A. Cooper P.K. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 10499-10503Crossref PubMed Scopus (215) Google Scholar, 52Cooper P.K. Nouspikel T. Clarckson S.G. Leadon S.A. Science. 1997; 275: 990-993Crossref PubMed Scopus (285) Google Scholar). Two other possibilities are that the in vitro assay may be forced by the free addition of recombinant CSB, and the levels of protein foundin vivo may necessitate the presence of CSA, or that the immunopurified pol II or baculovirus-purified CSB may have partially co-purified with endogenous CSA or an insect homologue.The recruitment of TFIIH to stalled pol II complexes is reminiscent of TFIIH recruitment to transcription initiation complexes, and draws an interesting analogy with the pol II general transcription factor TFIIE (Fig. 4, left). CSB can interact with a stalled pol II elongation complex and recruit TFIIH. Similarly, TFIIE interacts with the pol II initiation complex and recruits TFIIH in reconstituted systems (53Flores O. Lu H. Reinberg D. J. Biol. Chem. 1992; 267: 2786-2793Abstract Full Text PDF PubMed Google Scholar). TFIIE is also believed to modulate the enzymatic activities of TFIIH (8Lu H. Zawel L. Fisher L. Egly J.M. Reinberg D. Nature. 1992; 358: 641-645Crossref PubMed Scopus (329) Google Scholar, 11Drapkin R. Reardon J.T. Ansari A. Huang J.C. Zawel L. Ahn K. Sancar A. Reinberg D. Nature. 1994; 368: 769-772Crossref PubMed Scopus (407) Google Scholar, 54Ohkuma Y. Roeder R.G. Nature. 1994; 368: 160-163Crossref PubMed Scopus (138) Google Scholar), and help stabilize an open DNA configuration (19Holstege F.C. Tantin D. Carey M. van der Vliet P.C. Timmers H.T. EMBO J. 1995; 14: 810-819Crossref PubMed Scopus (130) Google Scholar). It will be interesting to determine whether or not the analogy can be extended to these phenomena as well.Two studies have found that XPA, the main NER damage recognition protein, has an affinity for TFIIH and recruits it to the site of damaged DNA (44Park C.-H. Mu D. Reardon J.T. Sancar A. J. Biol. Chem. 1995; 270: 4896-4902Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 45Nocetani S. Coin F. Saijo M. Tanaka K. Egly J.-M. J. Biol. Chem. 1997; 272: 22991-22994Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar) (Fig. 4, center). XPC also associates with TFIIH and is required for NER (center). One possibility is that in TCR the repair mechanism operates in reverse, that is, first by recruitment of TFIIH to the lesion site indirectly through pol II and CSB. The TFIIH-XPA interaction may then bring XPA proximal to the lesion site and increase the likelihood of XPA damage recognition (Fig. 4, right). This idea is supported by the finding that CSB can also interact with XPA (41Selby C.P. Sancar A. J. Biol. Chem. 1997; 272: 1885-1890Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar). The subsequent NER mechanism would then follow exactly as normal. Interestingly, XPC is not required for TCR (55Venema J. van Hoffen A. Karcagi V. Natarajan A.T. van Zeeland A.A. Mullenders L.H. Mol. Cell. Biol. 1991; 11: 4128-4134Crossref PubMed Scopus (289) Google Scholar). One intriguing possibility is that the CSB interaction surface on TFIIH is the same as or overlaps that for XPC, explaining the somewhat exclusive relationship between XPC and CSB.This facilitated repair system would not replace, but be superimposed upon the normal NER pathway in which XPA recognizes the DNA lesion directly, without a targeting mechanism. Recent results (56Selby C.P. Drapkin R. Reinberg D. Sancar A. Nucleic Acids Res. 1997; 25: 787-793Crossref PubMed Scopus (154) Google Scholar) indicate that a damaged region of DNA covered by pol II does not undergo reduced rates of repair, but rather is repaired normally. Thus a TFIIH recruitment mechanism would increase the baseline levels of repair that are already in place. In the above study, added purified CSA and CSB had no effect. 2D. Reinberg, personal communication. Perhaps a future system that includes the targeting step developed here may be applied toward recreating the entire coupling process with purified components, or toward the isolation of other components that are necessary for TCR. One advantage of this system is that only pol II need be added, so that the important roles of TFIIH can be addressed without a complicating requirement for transcription initiation.An interesting possibility is that the forms of TFIIH recruited during transcription initiation, NER, and TCR are different. In support of this idea, a highly purified and transcriptionally active 8-subunit TFIIH complex (kindly provided by J. and R. Conanway) cannot be recruited to the CSB-containing complex in labeled RNA-based gel mobility-shift assays. 3D. Tantin, unpublished observations.Although free of other general transcription factors, pol II, and XPG, the most purified TFIIH preparations used in these experiments may still contain auxiliary factors that aid in its recruitment. It should be noted that more highly purified preparations that have lost the XPA protein can also generate a supershift (data not shown).One or more factors not present in our assay system may also serve to further stabilize the aforementioned interactions or may act in later steps not modeled in our system, playing a key role in TCR in vivo. Candidate factors include TFIIE, TFIIF, XPG, and replication protein A. In addition the precise role of CSA remains to be deciphered. Furthermore, patients with manifestations of CS who do not fall into any “classic” complementation groups may harbor mutations in novel or unexpected genes encoding proteins that play an important role in this or related processes (57Itoh T. Ono T. Yamaizumi M. Mutat. Res. 1994; 314: 233-248Crossref PubMed Scopus (79) Google Scholar). Finally, because of the complexity of the CS phenotype, including neurological disorders and developmental abnormalities, and the heterogeneity of reports in the literature, it is likely that the CS proteins play important roles other than as recruitment factors for TFIIH. In this respect, it is interesting to note that preferential repair of oxidative damage can also be defective in CS (52Cooper P.K. Nouspikel T. Clarckson S.G. Leadon S.A. Science. 1997; 275: 990-993Crossref PubMed Scopus (285) Google Scholar), and that CSB interacts with the p53 protein in vitro (58Wang X.W. Yeh H. Schaeffer L. Roy R. Moncollin V. Egly J.M. Wang Z. Freidberg E.C. Evans M.K. Taffe B.G. Bohr V.A. Weeda G. Hoeijmakers J.H.J. Forrester K. Harris C.C. Nat. Genet. 1995; 10: 188-195Crossref PubMed Scopus (514) Google Scholar).3 Recent data further indicate a potential role for the CSB protein in transcription elongation (59Balajee A.S. May A. Dianov G.L. Friedberg E.C. Bohr V.A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 4306-4311Crossref PubMed Scopus (142) Google Scholar, 60Dianov G. Houle J.-F. Bohr V.A. Friedberg E.C. Nucleic Acids Res. 1997; 25: 3636-3642Crossref PubMed Scopus (64) Google Scholar, 61Selby C.P. Sancar A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 11205-11209Crossref PubMed Scopus (250) Google Scholar). Thus, the CS proteins may also be involved in targeting other repair factors, such as those involved in base excision repair, to active genes (62Nouspikel T. Lalle P. Leadon S.A. Cooper P.K. Clarkson S.G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3116-3121Crossref PubMed Scopus (143) Google Scholar), in targeting p53 to respond to damage in active genes (63Yamaizumi M. Sugano T. Oncogene. 1994; 9: 2775-2784PubMed Google Scholar), and be involved in the transcription process directly.Recently, it has been reported that simultaneous incubation of transcription and DNA repair templates with yeast extracts leads to a partial loss of transcription efficiency. The effect is dependent upon the CSB protein, and can be reversed by the addition of yeast TFIIH (64You Z. Feaver W.J. Friedberg E.C. Mol. Cell. Biol. 1998; 18: 2668-2676Crossref PubMed Scopus (35) Google Scholar). These results are fully consistent with those reported here. TFIIH1 is a complex factor capable of multiple functions (for review, see Hoeijmakerset al. (1Hoeijmakers J.H.J. Egly J.-M. Vermeulen W. Curr. Opin. Genet. Dev. 1996; 6: 26-33Crossref PubMed Scopus (155) Google Scholar)). It contains approximately nine subunits, although considerable compositional variability has been reported (2Svejstrup J.Q. Wang Z. Feaver W.J. Wu X. Bushnell D.A. Donahue T.F. Friedberg E.C. Kornberg R.D. 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