USP1-trapping lesions as a source of DNA replication stress and genomic instability

Kate E. Coleman, Yandong Yin, Sarah Kit Leng Lui, Sarah Keegan, David Fenyo, Duncan J. Smith, Eli Rothenberg and Tony T. Huang ()
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Kate E. Coleman: New York University School of Medicine
Yandong Yin: New York University School of Medicine
Sarah Kit Leng Lui: New York University School of Medicine
Sarah Keegan: New York University School of Medicine
David Fenyo: New York University School of Medicine
Duncan J. Smith: New York University
Eli Rothenberg: New York University School of Medicine
Tony T. Huang: New York University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract The deubiquitinase USP1 is a critical regulator of genome integrity through the deubiquitylation of Fanconi Anemia proteins and the DNA replication processivity factor, proliferating cell nuclear antigen (PCNA). Uniquely, following UV irradiation, USP1 self-inactivates through autocleavage, which enables its own degradation and in turn, upregulates PCNA monoubiquitylation. However, the functional role for this autocleavage event during physiological conditions remains elusive. Herein, we discover that cells harboring an autocleavage-defective USP1 mutant, while still able to robustly deubiquitylate PCNA, experience more replication fork-stalling and premature fork termination events. Using super-resolution microscopy and live-cell single-molecule tracking, we show that these defects are related to the inability of this USP1 mutant to be properly recycled from sites of active DNA synthesis, resulting in replication-associated lesions. Furthermore, we find that the removal of USP1 molecules from DNA is facilitated by the DNA-dependent metalloprotease Spartan to counteract the cytotoxicity caused by “USP1-trapping”. We propose a utility of USP1 inhibitors in cancer therapy based on their ability to induce USP1-trapping lesions and consequent replication stress and genomic instability in cancer cells, similar to how non-covalent DNA-protein crosslinks cause cytotoxicity by imposing steric hindrances upon proteins involved in DNA transactions.

Date: 2022
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DOI: 10.1038/s41467-022-29369-3

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