The XRCC1 phosphate-binding pocket binds poly (ADP-ribose) and is required for XRCC1 function

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Abstract

Poly (ADP-ribose) is synthesized at DNA singlestrandbreaks and can promote the recruitment of thescaffold protein, XRCC1. However, the mechanismand importance of this process has been challenged.To address this issue, we have characterized themechanism of poly (ADP-ribose) binding by XRCC1and examined its importance for XRCC1 function.Weshow that the phosphate-binding pocket in the centralBRCT1 domain of XRCC1 is required for selectivebinding to poly (ADP-ribose) at low levels of ADPribosylation, and promotes interaction with cellularPARP1. We also show that the phosphate-bindingpocket is required for EGFP-XRCC1 accumulationat DNA damage induced by UVA laser, H2O2, and atsites of sub-nuclear PCNA foci, suggesting that poly(ADP-ribose) promotes XRCC1 recruitment both atsingle-strand breaks globally across the genome andat sites of DNA replication stress. Finally, we showthat the phosphate-binding pocket is required followingDNA damage for XRCC1-dependent accelerationof DNA single-strand break repair, DNA base excisionrepair, and cell survival. These data support the hypothesisthat poly (ADP-ribose) synthesis promotesXRCC1 recruitment at DNA damage sites and is important for XRCC1 function.

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Breslin, C., Hornyak, P., Ridley, A., Rulten, S. L., Hanzlikova, H., Oliver, A. W., & Caldecott, K. W. (2015). The XRCC1 phosphate-binding pocket binds poly (ADP-ribose) and is required for XRCC1 function. Nucleic Acids Research, 43(14), 6934–6944. https://doi.org/10.1093/nar/gkv623

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