The single-strand DNA binding activity of human PC4 prevents mutagenesis and killing by oxidative DNA damage.
Human positive cofactor 4 (PC4) is a transcriptional coactivator with a highly conserved single-strand DNA (ssDNA) binding domain of unknown function. We identified PC4 as a suppressor of the oxidative mutator phenotype of the Escherichia coli fpg mutY mutant and demonstrate that this suppression requires its ssDNA binding activity. Saccharomyces cerevisiae mutants lacking their PC4 ortholog Sub1 are sensitive to hydrogen peroxide and exhibit spontaneous and peroxide-induced hypermutability. PC4 expression suppresses the peroxide sensitivity of the yeast sub1Delta mutant, suggesting that the human protein has a similar function. A role for yeast and human proteins in DNA repair is suggested by the demonstration that Sub1 acts in a peroxide resistance pathway involving Rad2 and by the physical interaction of PC4 with the human Rad2 homolog XPG. We show that XPG recruits PC4 to a bubble-containing DNA substrate with a resulting displacement of XPG and formation of a PC4-DNA complex. We discuss the possible requirement for PC4 in either global or transcription-coupled repair of oxidative DNA damage to mediate the release of XPG bound to its substrate.
Wang
Jen-Yeu
JY
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655. Michael.Volkert@umassmed.edu
Sarker
Altaf Hossain
AH
Cooper
Priscilla K
PK
Volkert
Michael R
MR
D016923:Cell Death; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004720:Endonucleases; D006801:Humans; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D016296:Mutagenesis; D009687:Nuclear Proteins; D018384:Oxidative Stress; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5
D004247:DNA; D004268:DNA-Binding Proteins; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5; C490043:IFRD2 protein, human; C073998:RAD2 protein, S cerevisiae