PRMT5 Genetic Interactions with DNA Double-Strand Break Repair Genes
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Date
2025-05
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The Ohio State University
Abstract
Homologous recombination (HR) and non-homologous end-joining (NHEJ) are important pathways for repairing DNA double-strand breaks (DSBs), which are critical for the maintenance of genomic stability. A hallmark of cancer cells is that they frequently harbor genetic mutations within the components of HR and NHEJ repair pathways, leading to genomic instability. Recent evidence suggests that targeting cancer cells with genetic defects in one repair pathway by inhibiting an alternate pathway offers therapeutic potential. Thus, investigating co-occurring mutations between genes offers insights into potential therapeutic avenues. PRMT5 is a protein arginine methyltransferase involved in chromatin remodeling and DSB repair, primarily through regulating the HR pathway. This study conducted a pan-cancer analysis with twenty-seven DSB repair genes, including the breast cancer susceptibility genes, BRCA1 and BRCA2, and the checkpoint genes, ATM and ATR. This pan-cancer analysis reveals that PRMT5 mutations frequently co-occur with these genes, particularly in cancers with high mutation burdens such as colorectal, lung, and skin cancers, suggesting that PRMT5 contributes to the destabilization of the DNA repair machinery, which promotes cellular transformation and immortalization. Remarkably, we observed a negative interaction between PRMT5 mutations and KAT5, a gene involved in chromosome remodeling. Chromosome remodeling is required for preparing broken ends for the HR machinery, and it precedes it. These co-mutations emphasize the role of PRMT5 as a critical modulator of DNA repair and propose its potential as a therapeutic target, particularly in cancers with KAT5 deficiencies. Inhibition of PRMT5 could potentially enhance the vulnerability of cancer cells with pre-existing KAT5 or other chromosome remodeling defects, presenting new opportunities for targeted cancer therapy.
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Keywords
Cancer, Genetics, Double Strand Breaks, Mutation