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

DAXX adds a de novo H3.3K9me3 deposition pathway to the histone chaperone network

“…Meanwhile, the HIRA complex associates with both ASF1 isoforms, consistent with our network analysis ( Figure 1 B) and a recent study. 67 …”

Autophosphorylation of the Tousled-like kinases TLK1 and TLK2 regulates recruitment to damaged chromatin via PCNA interaction

“…During homologous recombination, PCNA is loaded on the strand invaded D-loop and we speculate that this could result in the recruitment of TLK1 and TLK2 there for the regulation of repair factors at damaged chromatin, including RAD54 and ASF1 (34, 39, 61, 62). In line with a recent study, the hypersensitivity of TLK depletion implicates their potential involvement in homologous recombination repair(1).…”

Repair of DNA double-strand breaks leaves heritable impairment to genome function

“…How could successful repair of a DSB lesion lead to lasting topological changes? It has been shown that chromatin around a DSB undergoes a massive 3-D restructuring converging on transcriptionally silent domains that are, at least in part, defined by adjacent TAD boundaries and whose spatial arrangement related to the neighbouring TADs is stabilized by dedicated factors including the cohesin complex, 53BP1, RIF1 and SLFN5 genome caretakers, or ASF1 histone chaperone ( 24 , 28 , 30 , 31 , 63 ). These previous studies showed that DNA repair process per se can benefit from such chromatin restructuring (e.g.…”