2. Academic Validation
  3. FAM111A protects replication forks from protein obstacles via its trypsin-like domain

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

  • Nat Commun. 2020 Mar 12;11(1):1318. doi: 10.1038/s41467-020-15170-7.
Yusuke Kojima 1,  Yuka Machida 1,  Sowmiya Palani 2,  Thomas R Caulfield 3,  Evette S Radisky 4,  Scott H Kaufmann 1 5,  Yuichi J Machida 6 7
Affiliations

Affiliations

  • 1 Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
  • 2 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 55905, USA.
  • 3 Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
  • 4 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA.
  • 5 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA.
  • 6 Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. machida.yuichi@mayo.edu.
  • 7 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA. machida.yuichi@mayo.edu.
PMID: 32165630 DOI: 10.1038/s41467-020-15170-7
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.

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