Ubiquitinated PCNA drives USP1 synthetic lethality in cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA883979 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:CRISPR Cas9-based functional genomics screening is a powerful approach for identifying and characterizing novel oncology 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, pharmacological inhibition of USP1 leads to decreased DNA synthesis concomitant with the induction of S-phase-specific DNA damage. Genome-wide CRISPR-Cas9 screens identified RAD18 and UBE2K, which promote PCNA mono- and polyubiquitination respectively, as downstream mediators of USP1 dependency. The accumulation of mono- and polyubiquitinated PCNA following USP1 inhibition was associated with a reduction in total PCNA protein levels. Ectopic expression of WT and ubiquitin-dead K164R PCNA reversed USP1 inhibitor sensitivity. Our results demonstrate, 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 a novel subset of BRCA1/2 WT cancer enriched in ovarian and lung lineages. We further show PARP and USP1 inhibition are strongly synergistic in BRCA1/2 mutant cell lines and xenograft models. We postulate USP1 dependency unveils a previously uncharacterized vulnerability linked to post-translational modifications of PCNA. Taken together, USP1 inhibition may represent a unique therapeutic strategy for BRCA1/2 mutant tumors and a subset of BRCA1/2 WT tumors.
2022-09-27 | GSE214121 | GEO
Project description: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.
| S-EPMC9891357 | biostudies-literature
Project description:Assessment of synthetic lethality between an sml1 null mutation and Yeast Deletion mutations Keywords = SML1 Keywords = yeast Keywords = deletion Keywords = synthetic lethality Keywords = tag Keywords = barcode Keywords: repeat sample
2004-11-05 | GSE1765 | GEO
Project description:Assessment of synthetic lethality between an sgs1 null mutation and Yeast Deletion mutations Keywords = SGS1 Keywords = yeast Keywords = deletion Keywords = synthetic lethality Keywords = tag Keywords = barcode Keywords: repeat sample
2004-11-05 | GSE1757 | GEO
Project description:Assessment of synthetic lethality between a bim1 null mutation and Yeast Deletion mutations Keywords = BIM1 Keywords = yeast Keywords = deletion Keywords = synthetic lethality Keywords = tag Keywords = barcode Keywords: repeat sample
2004-11-05 | GSE1756 | GEO
Project description:Assessment of synthetic lethality between a cin8 deletion mutation and Yeast Deletion mutations. Keywords = CIN8 Keywords = yeast Keywords = deletion Keywords = synthetic lethality Keywords = tag Keywords = barcode Keywords: repeat sample
2004-11-05 | GSE1754 | GEO
Project description:Assessment of synthetic lethality between an overexpressed LCD1 gene and Yeast Deletion mutations Keywords = LCD1 Keywords = overexpression Keywords = yeast Keywords = deletion Keywords = synthetic lethality Keywords = tag Keywords = barcode Keywords: repeat sample
2004-11-05 | GSE1759 | GEO
Project description:Assessment of synthetic lethality between a temperature-sensitive allele of CDC102 and Yeast Deletion mutations Keywords: repeat sample
2004-11-05 | GSE1758 | GEO
Project description:Synthetic lethality is a type of genetic interaction in which two non-lethal mutations acting together result in a loss of viability. Such interactions are important for the insights they may offer into how gene functions are organized into distinct cellular processes. The datasets in this Series represent an effort to identify synthetic lethal genetic interactions in the yeast Saccharomyces cerevisiae on a genome-wide scale. Please see the Pubmed IDs in the individual Sample annotations.
2013-02-28 | E-GEOD-14217 | biostudies-arrayexpress
Project description:Obtain synthetic lethality/slow growth gene interactors of acs2-Ts8 Keywords: gene mutation
2006-10-01 | GSE4144 | GEO