2. Academic Validation
  3. Ubiquitinated PCNA Drives USP1 Synthetic Lethality in Cancer

Ubiquitinated PCNA Drives USP1 Synthetic Lethality in Cancer

  • Mol Cancer Ther. 2023 Feb 1;22(2):215-226. doi: 10.1158/1535-7163.MCT-22-0409.
Antoine Simoneau # 1,  Justin L Engel # 1,  Madhavi Bandi # 1,  Katherine Lazarides 1,  Shangtao Liu 1,  Samuel R Meier 1,  Ashley H Choi 1,  Hongxiang Zhang 1,  Binzhang Shen 1,  Lauren Martires 1,  Deepali Gotur 1,  Truc V Pham 1,  Fang Li 1,  Lina Gu 1,  Shanzhong Gong 1,  Minjie Zhang 1,  Erik Wilker 1,  Xuewen Pan 1,  Douglas A Whittington 1,  Scott Throner 1,  John P Maxwell 1,  Yingnan Chen 1,  Yi Yu 1,  Alan Huang 1,  Jannik N Andersen 1,  Tianshu Feng 1
Affiliations

Affiliation

  • 1 Tango Therapeutics, Boston, Massachusetts.
  • # Contributed equally.
PMID: 36228090 DOI: 10.1158/1535-7163.MCT-22-0409
Abstract

CRISPR Cas9-based screening is a powerful approach for identifying and characterizing novel drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating Enzyme USP1 in cancers with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors and a subset of BRCA1/2 wild-type (WT) tumors. In sensitive cells, pharmacologic inhibition of USP1 leads to decreased DNA synthesis concomitant with S-phase-specific DNA damage. Genome-wide CRISPR-Cas9 screens identify RAD18 and UBE2K, which promote PCNA mono- and polyubiquitination respectively, as mediators of USP1 dependency. The accumulation of mono- and polyubiquitinated PCNA following USP1 inhibition is associated with reduced PCNA protein levels. Ectopic expression of WT or ubiquitin-dead K164R PCNA reverses USP1 Inhibitor sensitivity. Our results show, for the first time, that USP1 dependency hinges on the aberrant processing of mono- and polyubiquitinated PCNA. Moreover, this mechanism of USP1 dependency extends beyond BRCA1/2 mutant tumors to selected BRCA1/2 WT Cancer cell lines enriched in ovarian and lung lineages. We further show PARP and USP1 inhibition are strongly synergistic in BRCA1/2 mutant tumors. We postulate USP1 dependency unveils a previously uncharacterized vulnerability linked to posttranslational modifications of PCNA. Taken together, USP1 inhibition may represent a novel therapeutic strategy for BRCA1/2 mutant tumors and a subset of BRCA1/2 WT tumors.

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