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

Yusuke Kojima, Yuka Machida, Sowmiya Palani, Thomas R. Caulfield, Evette S. Radisky, Scott H. Kaufmann and Yuichi J. Machida ()
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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
Yuichi J. Machida: Mayo Clinic

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15170-7

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