CRISPR/Cas9 Dropout Screen Identifies MEPCE as a Novel Vulnerability in BRCA1-mutated Cancers
Year: 2020
Type: dissertation
Abstract: The breast cancer susceptibility gene 1 (BRCA1) gene encodes a protein which primarily functions to maintain genomic integrity. Mutations in BRCA1 are associated with increased risk of developing breast (≥70%) and ovarian (≥40%) cancers. Additionally, tumors arising from BRCA1 mutations are typically high grade and recurrent in nature. Thus, there is an urgent need to identify novel optimal therapeutic options for the majority of these patients. Based on the principle of synthetic lethality, which refers to the loss of viability resulting from the disruption of two genes, which, individually, does not cause lethality, we performed a CRISPR-Cas9 dropout screen. Through our screen, we identified Methylphosphate Capping Enzyme (MEPCE) as a potential synthetic lethal interactor of BRCA1. Data collected in this study demonstrates that MEPCE is essential for restraining genomic instability in BRCA1-mutant cancers through attenuating R-loops and transcription-replication conflicts. We propose that MePCE inhibition should be investigated further as a potential therapeutic target for the treatment of BRCA1-associated cancer.
Source: TSpace (University of Toronto)
Author: Algouneh, Arash
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7133030935