XRCC1 mediates PARP1- and PAR-dependent recruitment of PARP2 to DNA damage sites.

Poly-ADP-ribose polymerases 1 and 2 (PARP1 and PARP2) are crucial sensors of DNA-strand breaks and emerging cancer therapy targets. Once activated by DNA breaks, PARP1 and PARP2 generate poly-ADP-ribose (PAR) chains on themselves and other substrates to promote DNA single-strand break repair (SSBR). PARP1 can be activated by diverse DNA lesions, whereas PARP2 specifically recognizes 5' phosphorylated nicks. They can be activated independently and provide mutual backup in the absence of the other. However, whether PARP1 and PARP2 have synergistic functions in DNA damage response remains elusive. Here, we show that PARP1 and the PAR chains generated by PARP1 recruit PARP2 to the vicinity of DNA damage sites through the scaffold protein XRCC1. Using quantitative live-cell imaging, we found that loss of XRCC1 markedly reduces irradiation-induced PARP2 foci in PARP1-proficient cells. The central BRCT domain (BRCT1) of XRCC1 binds to the PAR chain, while the C-terminal BRCT domain (BRCT2) of XRCC1 interacts with the catalytic domain of PARP2, facilitating its localization near the breaks. Together, these findings unveil a new function of XRCC1 in augmenting PARP2 recruitment in response to PARP1 activation and explain why PARP1, but not PARP2, is aggregated and hyperactivated in XRCC1-deficient cells.