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FAM111A protects replication forks from protein obstacles via its trypsin-like domain

Author

Listed:
  • Yusuke Kojima

    (Mayo Clinic)

  • Yuka Machida

    (Mayo Clinic)

  • Sowmiya Palani

    (Mayo Clinic)

  • Thomas R. Caulfield

    (Mayo Clinic)

  • Evette S. Radisky

    (Mayo Clinic)

  • Scott H. Kaufmann

    (Mayo Clinic
    Mayo Clinic)

  • Yuichi J. Machida

    (Mayo Clinic
    Mayo Clinic)

Abstract

Persistent protein obstacles on genomic DNA, such as DNA-protein crosslinks (DPCs) and tight nucleoprotein complexes, can block replication forks. DPCs can be removed by the proteolytic activities of the metalloprotease SPRTN or the proteasome in a replication-coupled manner; however, additional proteolytic mechanisms may exist to cope with the diversity of protein obstacles. Here, we show that FAM111A, a PCNA-interacting protein, plays an important role in mitigating the effect of protein obstacles on replication forks. This function of FAM111A requires an intact trypsin-like protease domain, the PCNA interaction, and the DNA-binding domain that is necessary for protease activity in vivo. FAM111A, but not SPRTN, protects replication forks from stalling at poly(ADP-ribose) polymerase 1 (PARP1)-DNA complexes trapped by PARP inhibitors, thereby promoting cell survival after drug treatment. Altogether, our findings reveal a role of FAM111A in overcoming protein obstacles to replication forks, shedding light on cellular responses to anti-cancer therapies.

Suggested Citation

  • Yusuke Kojima & Yuka Machida & Sowmiya Palani & Thomas R. Caulfield & Evette S. Radisky & Scott H. Kaufmann & Yuichi J. Machida, 2020. "FAM111A protects replication forks from protein obstacles via its trypsin-like domain," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15170-7
    DOI: 10.1038/s41467-020-15170-7
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    Cited by:

    1. Yilun Sun & Simone A. Baechler & Xiaohu Zhang & Suresh Kumar & Valentina M. Factor & Yasuhiro Arakawa & Cindy H. Chau & Kanako Okamoto & Anup Parikh & Bob Walker & Yijun P. Su & Jiji Chen & Tabitha Ti, 2023. "Targeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Liton Kumar Saha & Sourav Saha & Xi Yang & Shar-yin Naomi Huang & Yilun Sun & Ukhyun Jo & Yves Pommier, 2023. "Replication-associated formation and repair of human topoisomerase IIIα cleavage complexes," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Sowmiya Palani & Yuka Machida & Julia R. Alvey & Vandana Mishra & Allison L. Welter & Gaofeng Cui & Benoît Bragantini & Maria Victoria Botuyan & Anh T. Q. Cong & Georges Mer & Matthew J. Schellenberg , 2024. "Dimerization-dependent serine protease activity of FAM111A prevents replication fork stalling at topoisomerase 1 cleavage complexes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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