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

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 identified a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair.

Gene Regulatory Programs that Specify Age-Related Differences during Thymocyte Development

“…These findings suggest that neonates are more proliferative than adults at DN and SP8 stages of thymocyte development 23,[69][70][71] . Additionally, amongst the genes preferentially expressed in neonates, we identified genes relevant to chromatin organization, including H1f10 and Asf1b (Figures 2B and 2C) 72,73 . These observations suggest that neonates preferentially express genes that regulate chromatin organization and cell cycle regulation across thymocyte development.…”