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
  • 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. [email protected].
  • 7. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA. [email protected].
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.