Dimerization-dependent serine protease activity of FAM111A prevents replication fork stalling at topoisomerase 1 cleavage complexes

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 () and Yuichi J. Machida ()
Additional contact information
Sowmiya Palani: Mayo Clinic
Yuka Machida: Mayo Clinic
Julia R. Alvey: Mayo Clinic
Vandana Mishra: National Cancer Institute
Allison L. Welter: Mayo Clinic
Gaofeng Cui: Mayo Clinic
Benoît Bragantini: Mayo Clinic
Maria Victoria Botuyan: Mayo Clinic
Anh T. Q. Cong: Mayo Clinic
Georges Mer: Mayo Clinic
Matthew J. Schellenberg: Mayo Clinic
Yuichi J. Machida: Mayo Clinic

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract FAM111A, a serine protease, plays roles in DNA replication and antiviral defense. Missense mutations in the catalytic domain cause hyper-autocleavage and are associated with genetic disorders with developmental defects. Despite the enzyme’s biological significance, the molecular architecture of the FAM111A serine protease domain (SPD) is unknown. Here, we show that FAM111A is a dimerization-dependent protease containing a narrow, recessed active site that cleaves substrates with a chymotrypsin-like specificity. X-ray crystal structures and mutagenesis studies reveal that FAM111A dimerizes via the N-terminal helix within the SPD. This dimerization induces an activation cascade from the dimerization sensor loop to the oxyanion hole through disorder-to-order transitions. Dimerization is essential for proteolytic activity in vitro and for facilitating DNA replication at DNA-protein crosslink obstacles in cells, while it is dispensable for autocleavage. These findings underscore the role of dimerization in FAM111A’s function and highlight the distinction in its dimerization dependency between substrate cleavage and autocleavage.

Date: 2024
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DOI: 10.1038/s41467-024-46207-w

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