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bioRxiv · 10.1101/2021.11.19.469338

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

Xu, D.·Feng, S.·Ma, S.·Li, K.·Gao, S.·Ning, S.·Shang, J.·Guo, R.·Li, Q.·Blumenfeld, B.·Simon, I.
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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.

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Xu, D., Feng, S., Ma, S., Li, K., Gao, S., Ning, S., Shang, J., Guo, R., Li, Q., Blumenfeld, B., Simon, I.. 2021-11-19. RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity. https://doi.org/10.1101/2021.11.19.469338

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