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Xrcc1 interacts with the p58 subunit of dna pol α-primase and may coordinate dna repair and replication during s phase

Lévy, Nicolas
; 
Oehlmann, Maren
; 
Delalande, François
; 
Nasheuer, Heinz-Peter
; 
Van Dorsselaer, Alain
; 
Schreiber, Valérie
; 
de Murcia, Gilbert
; 
Ménissier-de Murcia, Josiane
; 
Maiorano, Domenico
; 
Bresson, Anne
Identifiers
http://hdl.handle.net/10379/12435
 https://doi.org/10.13025/27641
Publication Date
2009-03-21
Keywords
polymerase-alpha-primase, strand break repair, sister-chromatid exchange, xenopus egg extracts, cell-cycle, poly(adp-ribose) polymerase, damaged DNA, complex, proteins, parp-1
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Article
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Citation
Lévy, Nicolas; Oehlmann, Maren; Delalande, François; Nasheuer, Heinz Peter; Van Dorsselaer, Alain; Schreiber, Valérie; de Murcia, Gilbert; Ménissier-de Murcia, Josiane; Maiorano, Domenico; Bresson, Anne (2009). Xrcc1 interacts with the p58 subunit of dna pol α-primase and may coordinate dna repair and replication during s phase. Nucleic Acids Research 37 (10), 3177-3188
Abstract
Repair of single-stranded DNA breaks before DNA replication is critical in maintaining genomic stability; however, how cells deal with these lesions during S phase is not clear. Using combined approaches of proteomics and in vitro and in vivo proteinprotein interaction, we identified the p58 subunit of DNA Pol -primase as a new binding partner of XRCC1, a key protein of the single strand break repair (SSBR) complex. In vitro experiments reveal that the binding of poly(ADP-ribose) to p58 inhibits primase activity by competition with its DNA binding property. Overexpression of the XRCC1-BRCT1 domain in HeLa cells induces poly(ADP-ribose) synthesis, PARP-1 and XRCC1-BRCT1 poly(ADP-ribosyl)ation and a strong S phase delay in the presence of DNA damage. Addition of recombinant XRCC1-BRCT1 to Xenopus egg extracts slows down DNA synthesis and inhibits the binding of PCNA, but not MCM2 to alkylated chromatin, thus indicating interference with the assembly of functional replication forks. Altogether these results suggest a critical role for XRCC1 in connecting the SSBR machinery with the replication fork to halt DNA synthesis in response to DNA damage.
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Publisher
Oxford University Press (OUP)
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Attribution-NonCommercial-NoDerivs 3.0 Ireland
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Externally hosted open access publications with University of Galway authors (2)