Expression of Wild-type p53 Is Required for Efficient Global Genomic Nucleotide Excision Repair in UV-irradiated Human Fibroblasts

Abstract

We have shown previously that Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in the removal of UV-induced cyclobutane pyrimidine dimers from genomic DNA, but still proficient in the transcription-coupled repair pathway (Ford, J. M., and Hanawalt, P. C. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 8876–8880). We have now utilized monoclonal antibodies specific for cyclobutane pyrimidine dimers or 6-4 photoproducts, respectively, to measure their repair in UV-irradiated human fibroblasts. Cells homozygous for p53 mutations were deficient in the repair of both photoproducts, whereas cells heterozygous for mutant p53 exhibited normal repair of 6-4 photoproducts, but decreased initial rates of removal of cyclobutane pyrimidine dimers, compared with normal cells. The specificity of the effect of wild-type p53 on nucleotide excision repair was demonstrated in a p53 homozygous mutant cell line containing a tetracycline-regulated wild-type p53 gene. Wild-type p53 expression and activity were suppressed in the presence of tetracycline, whereas withdrawal of tetracycline resulted in the induction of p53 expression, cell cycle checkpoint activation, and DNA damage-induced apoptosis. The regulated expression of wild-type p53 resulted in the recovery of normal levels of repair of both cyclobutane pyrimidine dimers and 6-4 photoproducts in genomic DNA, but did not alter the transcription-coupled repair of cyclobutane pyrimidine dimers. Therefore, the wild-type p53 gene product is an important determinant of nucleotide excision repair activity in human cells. We have shown previously that Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in the removal of UV-induced cyclobutane pyrimidine dimers from genomic DNA, but still proficient in the transcription-coupled repair pathway (Ford, J. M., and Hanawalt, P. C. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 8876–8880). We have now utilized monoclonal antibodies specific for cyclobutane pyrimidine dimers or 6-4 photoproducts, respectively, to measure their repair in UV-irradiated human fibroblasts. Cells homozygous for p53 mutations were deficient in the repair of both photoproducts, whereas cells heterozygous for mutant p53 exhibited normal repair of 6-4 photoproducts, but decreased initial rates of removal of cyclobutane pyrimidine dimers, compared with normal cells. The specificity of the effect of wild-type p53 on nucleotide excision repair was demonstrated in a p53 homozygous mutant cell line containing a tetracycline-regulated wild-type p53 gene. Wild-type p53 expression and activity were suppressed in the presence of tetracycline, whereas withdrawal of tetracycline resulted in the induction of p53 expression, cell cycle checkpoint activation, and DNA damage-induced apoptosis. The regulated expression of wild-type p53 resulted in the recovery of normal levels of repair of both cyclobutane pyrimidine dimers and 6-4 photoproducts in genomic DNA, but did not alter the transcription-coupled repair of cyclobutane pyrimidine dimers. Therefore, the wild-type p53 gene product is an important determinant of nucleotide excision repair activity in human cells. Discovery and Characterization of DNA Excision Repair Pathways: the Work of Philip Courtland HanawaltJournal of Biological ChemistryVol. 285Issue 34PreviewExpression of Wild-type p53 Is Required for Efficient Global Genomic Nucleotide Excision Repair in UV-irradiated Human Fibroblasts (Ford, J. M., and Hanawalt, P. C. (1997) J. Biol. Chem. 272, 28073-28080) Full-Text PDF Open Access The molecular mechanisms that regulate the responses of normal and neoplastic human cells to DNA damage are critical determinants for the biological end points of mutagenesis and cell death. The p53 tumor suppressor gene plays a central role in mediating the cellular responses to DNA damage in mammalian cells, as demonstrated by its ability to regulate cell cycle progression and programmed death in cells exposed to DNA damaging agents (1Kastan M.B. Onyekwere O. Sidransky D. Vogelstein B. Craig R.W. Cancer Res. 1991; 51: 6304-6311PubMed Google Scholar, 2Kuerbitz S.J. Plunkett B.S. Walsh W.V. Kastan M.B. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 7491-7495Crossref PubMed Scopus (1848) Google Scholar, 3Lane D.P. Nature. 1992; 358: 15-16Crossref PubMed Scopus (4544) Google Scholar, 4Fritsche M. Haessler C. Brandner G. Oncogene. 1993; 8: 307-318PubMed Google Scholar). A wide variety of endogenous and exogenous agents cause damage to DNA, and multiple enzymatic processes exist to repair these different lesions. The most versatile and ubiquitous mechanism for DNA repair is nucleotide excision repair (NER), 1The abbreviations used are: NER, nucleotide excision repair; CPD, cyclobutane pyrimidine dimer; LFS, Li-Fraumeni syndrome; wt, wild-type; mut, mutant; TEV, T4 endonuclease V; DHFR, dihydrofolate reductase; Tet, tetracycline; XP, xeroderma pigmentosum; PBS, phosphate-buffered saline; BrdUrd, 5-bromodeoxyuridine. which operates to remove many types of lesions, including UV-induced cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine-pyrimidone photoproducts (hereafter referred to as 6-4 photoproducts). Such lesions may pose as structural blocks to transcription and replication, and they may also result in mutations if translesional replication occurs or if they are not repaired correctly. NER is heterogeneous within the mammalian genome, and CPDs are more efficiently removed from actively expressed genes than from unexpressed regions of the genome (5Bohr V.A. Smith C.A. Okumoto D.S. Hanawalt P.C. Cell. 1985; 40: 359-369Abstract Full Text PDF PubMed Scopus (1015) Google Scholar, 6Mellon I. Bohr V.A. Smith C.A. Hanawalt P.C. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 8878-8882Crossref PubMed Scopus (380) Google Scholar). Generally, the transcribed strand of an active gene is repaired more rapidly than the non-transcribed strand (7Mellon I. Spivak G. Hanawalt P.C. Cell. 1987; 51: 241-249Abstract Full Text PDF PubMed Scopus (1044) Google Scholar), a process termed transcription-coupled repair. In normal human cells, both CPDs and 6-4 photoproducts are removed from genomic, non-transcribed DNA through a pathway referred to as global genomic NER. We and others have presented evidence for a direct role for p53 in NER, potentially unrelated to cell cycle and cell death events (8Ford J.M. Hanawalt P.C. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar, Oncogene. Google Scholar, J.M. Bohr V.A. PubMed Scopus Google Scholar). the of mutations in the p53 gene on NER and cellular to were in human fibroblasts from with the Li-Fraumeni syndrome which were heterozygous for mutations in of and in mutant p53 (8Ford J.M. Hanawalt P.C. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). The p53 homozygous mutant cells were more to and exhibited UV-induced than did the p53 heterozygous mutant cells or than normal fibroblasts wild-type the p53 homozygous mutant cells were deficient in the global genomic NER of CPDs compared with normal cells or to p53 heterozygous mutant cells. the of repair of the non-transcribed of the actively expressed dihydrofolate gene and the p53 gene in p53 homozygous mutant cells was decreased to that in normal with the decreased genomic repair the p53 homozygous mutant cells the ability to transcription-coupled repair. p53 homozygous mutant cells were deficient in global genomic NER of whereas transcription-coupled repair the effect of of p53 on global genomic NER, used a different for the of removal of both CPDs and 6-4 photoproducts from genomic DNA of UV-irradiated cells. previously used of T4 endonuclease DNA to measure removal of have now utilized monoclonal antibodies which CPDs and 6-4 photoproducts to measure their of removal from human fibroblasts that are or mutant for the p53 gene. to the role of the p53 gene product in NER, of both global and transcription-coupled repair have in a p53 homozygous mutant cell line containing a tetracycline p53 gene. that of p53 activity in a in the global genomic NER of both CPDs and 6-4 photoproducts, but not transcription-coupled repair of and that the expression of p53 in a p53 mutant human cell line in of normal levels of global genomic repair of both photoproducts, as as cell cycle and human fibroblasts were as in with and in cell from M. D. Cancer from (hereafter termed and were cell heterozygous for mutations in p53 and Cell. 1992; Full Text PDF PubMed Scopus Google Scholar). of cell line homozygous for mutant p53 have and are termed and mut, (8Ford J.M. Hanawalt P.C. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). normal human which wild-type were from the Human for cells from a with xeroderma were from S. D. Proc. Natl. Acad. Sci. U. S. A. 1987; PubMed Scopus Google Scholar). cells, by were from cells which a for expression of p53 was A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). were and a of p53 expression was for in and termed cell line was in the presence of and to for the containing the p53 with the and the with the cells were in the presence of of p53 expression was of p53 and (hereafter termed cellular was by cells in a of and The cells were for and the were by the and of were by Nature. PubMed Scopus Google and to a J. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). was by the for with monoclonal antibodies to human by in and human by in by the for with by in were and to the The of were by of The of CPDs and 6-4 photoproducts in genomic DNA from cells was an cells were with with PBS, and with a Cells were or in for cells were in a containing and Genomic DNA was by and and DNA and specific were DNA was by for and on the monoclonal antibodies photoproducts in and of genomic DNA from in and were to a in a of for of of for of 6-4 photoproducts). of genomic DNA from cells were also for to for DNA of the monoclonal The was for with monoclonal antibodies specific for CPDs or 6-4 photoproducts a of in by M. M. O. 1991; PubMed Scopus Google Scholar). a of in PBS, and were for the DNA to of the was by of from the from DNA from different for cell line were and exhibited than Repair of CPDs was within the transcribed and non-transcribed strand of the the central of the previously (7Mellon I. Spivak G. Hanawalt P.C. Cell. 1987; 51: 241-249Abstract Full Text PDF PubMed Scopus (1044) Google J.M. Hanawalt P.C. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). Cells were UV-irradiated with for an initial or in containing to DNA, and was repair to DNA to by C.A. Hanawalt P.C. Hanawalt P.C. DNA A of Scholar). The of induction of CPDs and their of removal from the transcribed and non-transcribed of the human gene was by DNA with TEV, and the of the in DNA from cells to remove CPDs from their from were or with TEV, in to a and with by transcription in of the (8Ford J.M. Hanawalt P.C. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). The of in the and was by and was used to the of CPDs the of cell cycle and both and cells were and in in PBS, with and with cells were for DNA a The of cells in and was an if resulted in of cells were or not with for in in PBS, with the DNA and Cells were to if they the cells that of DNA the of their cell and cell to in The effect of on p53 levels and activity in normal human fibroblasts and in the p53 homozygous mutant human cell from was by of from cells and with monoclonal antibodies to p53 and to which is regulated by p53 J.M. D. Vogelstein B. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). In normal human cells, p53 levels were by with levels and In levels of were also by a cells a of the p53 in a Cancer PubMed Scopus Google Scholar). of from these cells demonstrated p53 to or induction of the gene product cells a of the p53 gene Cancer PubMed Scopus Google Scholar). of from these cells demonstrated of the mutant both to and but induction of the gene product Therefore, of normal human fibroblasts in a and induction of p53 levels and in human induction of expression to p53 The induction and repair of UV-induced CPDs and 6-4 photoproducts in genomic DNA was an and monoclonal antibodies specific to these lesions. human fibroblasts containing p53 efficiently repaired both CPDs and 6-4 photoproducts, a of 6-4 photoproducts than CPDs as from C.A. J.M. Res. 1985; PubMed Scopus Google Scholar). a repair in human fibroblasts mutant for the gene was also The gene product is for global genomic NER, but not for the transcription-coupled repair pathway J.M. Hanawalt P.C. Google as these cells levels of removal of both CPDs and 6-4 photoproducts cell homozygous for p53 mutations a and of repair of both UV-induced photoproducts compared with normal cells. Repair of CPDs in these cells was than in the cells repair of 6-4 photoproducts was than in the cells, but than in normal cells cell heterozygous for mutant p53 exhibited normal repair of 6-4 photoproducts, but decreased initial rates of removal of compared with normal cells. the specificity of p53 for of global genomic NER and a of the cell line was in which the expression of p53 In cell or induction of p53 activity was by cells with levels of In the presence of Tet, p53 and levels were to the cell line withdrawal of Tet, p53 levels by levels gene expression was also by Therefore, p53 expression and activity were in cell line by withdrawal of in the presence of Tet, did not and levels if cells were UV-irradiated withdrawal of Tet, a and in p53 and levels the of the p53 gene in cell the of on p53 processes were of the most of p53 is the of DNA replication DNA We DNA replication in UV-irradiated cells. Cells were with DNA was from DNA by C.A. Hanawalt P.C. Hanawalt P.C. DNA A of Scholar). in the presence of Tet, a of DNA replication within of whereas withdrawal of and induction of DNA replication was of cells was to the of withdrawal and on cell cycle withdrawal of and induction of cells exhibited a in cells in both the and and a in cells in A in was by the DNA In the presence of Tet, UV-irradiated cells did not DNA damage-induced of DNA replication, or In induction of UV-irradiated cells an in cells in and from to as as a in DNA The effect of p53 induction on UV-induced in cells was by of cells. In the presence of Tet, effect on the of cells withdrawal of and induction of a in the of cells with was Therefore, the of levels of in cells for the of p53 as as of of the cellular of p53 including of induction of cell cycle of DNA replication DNA and DNA damage-induced apoptosis. Therefore, cell line was for of the effect of p53 expression and on the cellular of UV-induced DNA The effect of p53 activity on the repair of CPDs and 6-4 photoproducts in genomic DNA, and the repair of CPDs in of the gene was in cells in the presence or of In the presence of Tet, cells removed than of CPDs from genomic DNA within to the cells cells were withdrawal of Tet, cells removed of the CPDs from genomic DNA within the cells were with the removal of Tet, a was not The removal of 6-4 photoproducts from genomic DNA withdrawal of with to that for normal fibroblasts. In the presence of Tet, removal was repair of 6-4 photoproducts by in the presence of Tet, the cells exhibited more repair of 6-4 photoproducts than the cells repair from levels of p53 expression in the cells in the presence of Tet, which may the removal of 6-4 photoproducts, but not alter the repair of We demonstrated previously that both the and cells were also deficient in CPDs from the non-transcribed strand of the p53 and with their in global genomic NER. both these cell the ability to repair the transcribed strand of these expressed genes in a to p53 cells (8Ford J.M. Hanawalt P.C. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). that of removal from the non-transcribed strand was to the p53 repair of CPDs within of the human gene was in cells in the presence or of Tet, and was that the presence or of effect on repair of CPDs within the transcribed strand of the presence of a on the of removal of CPDs from the non-transcribed strand of in the presence of Tet, of CPDs were removed from the non-transcribed strand of the gene by an to that for the cells (8Ford J.M. Hanawalt P.C. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). withdrawal of and induction of repair of the non-transcribed strand a normal a decreased compared with the transcribed as previously for many normal human fibroblasts (8Ford J.M. Hanawalt P.C. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar, J.M. Hanawalt P.C. PubMed Scopus Google for removal of CPDs from the gene in human fibroblasts. with to the gene was on DNA from cells with as demonstrated in The of induction of CPDs and their of removal from the transcribed and non-transcribed of the human gene were by the of specific in DNA from cells to remove from their The of in the and was by and was used to the of CPDs The points on the the repair from biological with with an specific for the transcribed or non-transcribed strand of the human in the presence or of Therefore, expression of p53 in p53 human fibroblasts in recovery of normal levels of global genomic NER and repair of lesions within the non-transcribed strand of expressed that have previously shown to in p53 mutant cells. that levels of p53 not the of transcription-coupled which have shown previously to by of p53 in human fibroblasts. evidence that the human p53 tumor suppressor gene is in the of NER activity in human cells, in We have global genomic NER of UV-induced CPDs and 6-4 photoproducts, as as transcription-coupled repair of CPDs from of the in human fibroblasts or mutant for p53 and in human p53 mutant fibroblasts in which the expression of a p53 gene was initial of the DNA with of p53 (8Ford J.M. Hanawalt P.C. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar), and that the p53 gene product is in the of global genomic NER, but not transcription-coupled of UV-induced DNA We previously that mutations in the p53 gene resulted in a in global genomic DNA repair of CPDs in and cells (8Ford J.M. Hanawalt P.C. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). these and to the effect of p53 mutations on global genomic NER more an monoclonal antibodies specific to of the UV-induced DNA CPDs and 6-4 with are with previously for that of p53 is with a in the global genomic repair of in to that in cells. In that p53 homozygous mutant cells are also deficient in the repair of UV-induced 6-4 photoproducts, not to the exhibited by cells. with p53 heterozygous mutant cells a in the initial of removal of CPDs from genomic DNA, repair was normal by and repair of 6-4 photoproducts was normal the repair in these p53 homozygous mutant cells were to of than to in these cells, cells in which the expression of p53 The of these human fibroblasts for for with resulted in the of p53 gene expression and In withdrawal of resulted in the induction of p53 levels and to an and in a to that for endogenous p53 DNA Therefore, these cells to the effect of p53 expression and on NER. an for global genomic NER, demonstrated in cells that the regulated expression of p53 in a p53 resulted in the of normal levels of repair of both CPDs and 6-4 photoproducts, compared with their p53 homozygous mutant cells or to the cells in the presence of The of 6-4 repair in cells in the presence of compared with cells that levels of p53 are for repair The in the of p53 and biological activity for of normal global genomic repair of 6-4 photoproducts compared with CPDs mechanisms for the role of p53 in NER, as The effect of p53 levels on repair of CPDs in the transcribed and non-transcribed strand of the human gene was also in cells. In of (8Ford J.M. Hanawalt P.C. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar), p53 expression was not for transcription-coupled repair of the and of removal of CPDs from the transcribed strand of the gene was in cells in the or presence of Tet, and to that in normal human fibroblasts. In the removal of CPDs from the non-transcribed strand of the gene was deficient in cells, to for repair of the non-transcribed strand of both and p53 in the cells (8Ford J.M. Hanawalt P.C. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). withdrawal of from cells, repair of CPDs in the non-transcribed strand of was to wild-type the role of p53 in repair of lesions within genomic DNA, repair of the non-transcribed of expressed genes the of cells to repair non-transcribed DNA J.M. Hanawalt P.C. Google Scholar). with initial of the specific NER in human the effect of p53 activity on NER in these cells, and in cells mutant for In these are with that of p53 in a in global genomic NER, but effect on transcription-coupled repair. and Oncogene. Google A. Oncogene. Google have presented of evidence that in p53 activity normal NER of human cells containing p53 with genes the of which or p53 as a mutant human or resulted in a in the ability of cells to a gene within an UV-irradiated that these cells. In to in the cells also were deficient in DNA compared with the cells A. Oncogene. Google Scholar). evidence a role for p53 in global genomic NER activity by PubMed Scopus Google Scholar), in an of cell of different than used in the and containing p53 mutations to a effect p53 DNA activity A. S. Cancer Res. 1993; Google Scholar). of genomic NER was by of DNA from UV-irradiated cells in which DNA NER was A of repair events in DNA of were in the cell compared with normal fibroblasts Repair in p53 and also with in or from multiple of a mutant p53 or from in which p53 decreased global genomic repair of both CPDs and 6-4 photoproducts as monoclonal antibodies and to in G. V.A. J. Google Scholar, G. V.A. J. Google Scholar). In to by that p53 activity may also effect the of transcription-coupled repair. in the to of the have the effect of p53 expression transcription-coupled repair by the removal of UV-irradiated DNA damage from the transcribed strand of an endogenous gene. J.M. Bohr V.A. PubMed Scopus Google a in the of removal of CPDs from the gene in human which were heterozygous for p53 and that was to decreased transcription-coupled repair. these used a DNA to DHFR, than as to repair within of the and their an of repair within the transcribed strand and the non-transcribed strand genomic of gene. Therefore, these are with a in global genomic repair in decreased removal of CPDs from the non-transcribed strand of DHFR, as have In the that was in the recovery of that transcription-coupled repair was in these cells. were also by PubMed Scopus Google in fibroblasts containing the p53 by and a to decreased removal of CPDs from the gene. of these the removal of lesions from the transcribed strand of an expressed gene of transcription-coupled they an repair from both which may to both and transcription-coupled repair. is evidence to that in p53 activity have effect on transcription-coupled repair. We that gene expression was regulated by p53 in transcription-coupled repair in p53 homozygous mutant cells. of DNA repair within a endogenous gene is to the effect of p53 mutations on global genomic NER repair The of human p53 heterozygous mutant fibroblasts a in NER We previously that fibroblasts heterozygous for a or a both a in global genomic repair of CPDs points but normal repair by as by the (8Ford J.M. Hanawalt P.C. Proc. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). of the repair of both CPDs and 6-4 photoproducts in these cell by also a in the initial of repair of but normal levels of 6-4 compared with that in p53 cells. the removal of CPDs from the non-transcribed strand of the gene in cells a in the initial but normal of removal not and Oncogene. Google have these p53 heterozygous mutant cells and that they may of as in a in of the gene. that or types of mutations within the p53 gene may with a more or effect on the activity of the p53 D.P. PubMed Scopus Google Scholar). also with NER activity a in the removal of CPDs from both of the or with a in repair of the non-transcribed in p53 heterozygous fibroblasts mutant J.M. Bohr V.A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). the to which repair was deficient was than in p53 heterozygous cell containing different p53 the is to a effect on p53 DNA activity A. S. Cancer Res. 1993; Google Scholar, A. S. Oncogene. 1993; 8: Google Scholar). Therefore, mutations within the p53 gene may a effect on the with to NER activity than in the cell in of a direct of these cell that global genomic NER from transcription-coupled and with the effect of different p53 mutations on p53 is that a p53 gene effect and that of mutant p53 gene expression result in global genomic NER. The mechanism for the effect of p53 expression on global genomic NER activity is not the multiple with the p53 and the molecular in which p53 is for of responses to to its ability to regulate the of of for NER the and both of which expression in a p53 J. M. Kastan M.B. S.J. Vogelstein B. Cancer Res. Google Scholar, M.B. Walsh W.V. Plunkett B.S. Vogelstein B. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar). and may alter in of excision repair I. Kastan M.B. PubMed Scopus Google Scholar, A. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and that to the ability of these to to cell a in both DNA and repair the effect of or on genomic repair processes to is that p53 many genes as and may potentially in expression of NER or We that p53 may regulate the transcription or activity of gene to in NER J.M. Hanawalt P.C. Google Scholar). are genes to in the of lesions in genomic DNA, for of the repair to lesions in or for of DNA to repair the Hanawalt P.C. Res. 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PubMed Scopus Google and DNA S. B. A. J. Cell. Full Text PDF PubMed Scopus Google Scholar). have that p53 or to photoproducts or lesions by NER the from repair that a direct or of p53 is not in NER have that the of p53 to in NER of a DNA J.M. B. J. PubMed Scopus Google Scholar, A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is important to that these not the cellular of p53 activity on NER, the of p53 on of in of In that of p53 in human fibroblasts is with a in NER of and non-transcribed DNA, but not repair of the transcribed of expressed the regulated expression of p53 in these p53 mutant fibroblasts in of a normal repair the specific mechanism by which p53 repair is not these a cellular for the p53 in to its role in cell cycle and apoptosis. We that in NER of UV-induced DNA damage with mutant p53 are to a direct effect of or of a on the of the or activity of or more repair We A. and C. A. Smith for and critical of the and for with