Abstract
The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors. However, it is unclear how this pathway suppresses initiation of resection. Here, we identify ASF1 as a partner of RIF1 via an interacting manner similar to its interactions with histone chaperones CAF-1 and HIRA. ASF1 is recruited to distal chromatin flanking DNA breaks by 53BP1-RIF1 and promotes non-homologous end joining (NHEJ) using its histone chaperone activity. Epistasis analysis shows that ASF1 acts in the same NHEJ pathway as RIF1, but via a parallel pathway with the shieldin complex, which suppresses resection after initiation. Moreover, defects in end resection and homologous recombination (HR) in BRCA1-deficient cells are largely suppressed by ASF1 deficiency. Mechanistically, ASF1 compacts adjacent chromatin by heterochromatinization to protect broken DNA ends from BRCA1-mediated resection. Taken together, our findings identify a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair.
Highlights
The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors
We find that ASF1 forms a complex with RIF1 in response to DNA damage through a B-domain, which is responsible for the interactions of CAF-1 and HIRA with ASF1
ASF1 was absent (Supplementary Fig. 10g). These results suggest that 53BP1-RIF1–ASF1-mediated heterochromatinization may occur at common Double-strand breaks (DSBs) sites
Summary
The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors. It is unclear how this pathway suppresses initiation of resection. ASF1 is recruited to distal chromatin flanking DNA breaks by 53BP1-RIF1 and promotes nonhomologous end joining (NHEJ) using its histone chaperone activity. Our findings identify a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair. ASF1 promotes formation of high-order chromatin structure, antagonizes BRCA1-dependent DNA end resection and stimulates NHEJ via its histone chaperone activity. We identify a RIF1-ASF1 histone chaperone complex that protects broken DNA ends in a parallel pathway with shieldin and confers PARPi sensitivity on BRCA1-deficient cells
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