XRCC1 and DNA polymerase beta interaction contributes to cellular alkylating-agent resistance and single-strand break repair.
X-ray cross complementing 1 (XRCC1) protein has been suggested to bind to DNA single-strand breaks (SSBs) and organize protein interactions that facilitate efficient DNA repair. Using four site-specifically modified human XRCC1 mutant expression systems and functional complementation assays in Chinese hamster ovary (CHO) XRCC1-deficient EM9 cells, we evaluated the cellular contributions of XRCC1s proposed N-terminal domain (NTD) DNA binding and DNA polymerase beta (POLbeta) interaction activities. Results within demonstrate that the interaction with POLbeta is biologically important for alkylating agent resistance and SSB repair, whereas the proposed DNA binding function is not critical to these phenotypes. Our data favor a model where the interaction of XRCC1 with POLbeta contributes to efficient DNA repair in vivo, whereas its interactions with target DNA is biologically less relevant.
Wong
Heng-Kuan
HK
Laboratory of Molecular Gerontology, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA.
Wilson
David M
DM
D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004249:DNA Damage / Q000187:drug effects*; D019951:DNA Polymerase beta / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance; D006801:Humans; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D000076105:X-ray Repair Cross Complementing Protein 1
D000477:Alkylating Agents; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D008741:Methyl Methanesulfonate; D019951:DNA Polymerase beta