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

Sumin Feng, Sai Ma, Kejiao Li, Shengxian Gao, Shaokai Ning, Jinfeng Shang, Ruiyuan Guo, Yingying Chen, Britny Blumenfeld, Itamar Simon, Qing Li, Rong Guo and Dongyi Xu ()
Additional contact information
Sumin Feng: Peking University
Sai Ma: Peking University
Kejiao Li: Peking University
Shengxian Gao: Peking University
Shaokai Ning: Peking University
Jinfeng Shang: Peking University
Ruiyuan Guo: Peking University
Yingying Chen: Peking University
Britny Blumenfeld: The Hebrew University
Itamar Simon: The Hebrew University
Qing Li: Peking University
Rong Guo: Peking University
Dongyi Xu: Peking University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28588-y

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