RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity

The 53BP1-RIF1 pathway is important for DNA repair. Here, the authors identified the histone chaperone ASF1, which functions as a suppressor of DNA end resection through changing high-order chromatin structure, as a partner of RIF1. This finding links DNA repair and dynamic changes of high-order chromatin structure. 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.

Automated summary

The study identifies the histone chaperone ASF1 as a partner of RIF1 in the 53BP1-RIF1 pathway, linking DNA repair and changes in chromatin structure. ASF1 is recruited to chromatin flanking DNA breaks and promotes non-homologous end joining (NHEJ) through its histone chaperone activity. ASF1 acts in the same NHEJ pathway as RIF1, but through a parallel pathway with the shieldin complex. ASF1 deficiency suppresses defects in end resection and homologous recombination in BRCA1-deficient cells. Mechanistically, ASF1 compacts adjacent chromatin to protect DNA ends from resection. The findings reveal the importance of the RIF1-ASF1 complex in stimulating NHEJ for DNA repair.