Details

Autor(en) / Beteiligte

• Simoneau, Antoine
• Engel, Justin L
• Bandi, Madhavi
• Lazarides, Katherine
• Liu, Shangtao
• Meier, Samuel R
• Choi, Ashley H
• Zhang, Hongxiang
• Shen, Binzhang
• Martires, Lauren
• Gotur, Deepali
• Pham, Truc V
• Li, Fang
• Gu, Lina
• Gong, Shanzhong
• Zhang, Minjie
• Wilker, Erik
• Pan, Xuewen
• Whittington, Douglas A
• Throner, Scott
• Maxwell, John P
• Chen, Yingnan
• Yu, Yi
• Huang, Alan
• Andersen, Jannik N
• Feng, Tianshu

Titel

Ubiquitinated PCNA Drives USP1 Synthetic Lethality in Cancer

Ist Teil von

• Molecular cancer therapeutics, 2023-02, Vol.22 (2), p.215-226

Ort / Verlag

United States

Erscheinungsjahr

2023

Quelle

Elektronische Zeitschriftenbibliothek (Open access)

Beschreibungen/Notizen

• 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.