Chk1 promotes non-homologous end joining in G1 through direct phosphorylation of ASF1A

The cell-cycle phase is a major determinant of repair pathway choice at DNA double strand breaks, non-homologous end joining (NHEJ), or homologous recombination (HR). Chk1 responds to genotoxic stress in S/G2 phase, but here, we report a role of Chk1 in directly promoting NHEJ repair in G1 phase. ASF1A is a histone chaperone, but it promotes NHEJ through a pathway independent of its histone-chaperone activity. Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks. Chk1 deficiency suppresses all steps downstream of MDC1 following a DNA break in G1, namely histone ubiquitination, 53BP1 localization to the DNA break, and NHEJ. Thus, ASF1A phosphorylation by Chk1 is essential for DNA break repair by NHEJ in G1.

Automated summary

The cell-cycle phase plays a crucial role in determining repair pathway choice at DNA double-strand breaks, with Chk1 promoting non-homologous end joining (NHEJ) repair in the G1 phase. ASF1A, a histone chaperone, also promotes NHEJ independently of its chaperone activity. Chk1 phosphorylates ASF1A at Ser-166 in G1, enhancing its interaction with the repair protein MDC1 and promoting NHEJ repair.