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

Author

Listed:
  • 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
    Peking University)

  • Rong Guo

    (Peking University)

  • Dongyi Xu

    (Peking University)

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.

Suggested Citation

  • Sumin Feng & Sai Ma & Kejiao Li & Shengxian Gao & Shaokai Ning & Jinfeng Shang & Ruiyuan Guo & Yingying Chen & Britny Blumenfeld & Itamar Simon & Qing Li & Rong Guo & Dongyi Xu, 2022. "RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28588-y
    DOI: 10.1038/s41467-022-28588-y
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