Matthew S Gillespie, Kelly Chiang, Gemma L Regan-Mochrie, Soo-Youn Choi, Ciara M Ward, Debashish Sahay, Paloma Garcia, Roland Arnold, Clare C Davies
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引用次数: 0
Abstract
Breast cancer stem cells (BCSCs) are a rare cell population that is responsible for tumour initiation, metastasis and chemoresistance. Despite this, the mechanism by which BCSCs withstand genotoxic stress is largely unknown. Here, we uncover a pivotal role for the arginine methyltransferase PRMT5 in mediating BCSC chemoresistance by modulating DNA repair efficiency. Mechanistically, we identify PRMT5 as a major regulator of DNA damage response (DDR) gene splicing in BCSCs, particularly those integral to the Fanconi Anaemia and homologous recombination pathways, with PRMT5 inhibition synergising with chemotherapy to promote BCSC apoptosis. A comparison of BCSCs and their bulk cell progeny identified some shared (ATM, DDX11, EXO1, FAN1, SLX4) but many unique (ATR, RAD17, RAD51D, RUVBL1) PRMT5-dependent alternative DDR splicing events. Surprisingly, these skipped exons and retained intron events rarely lead to substantial gene expression repression, suggesting that PRMT5 inhibition predominantly results in nuclear detention of intron-containing transcripts and the production of non-canonical isoforms with compromised protein function. Since many genes within the same DDR pathway undergo deregulated splicing, this study thus reveals additional points of vulnerability and alternative combination drug strategies that could improve the therapeutic efficacy of PRMT5 inhibitors to promote BCSC eradication.
期刊介绍:
Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge.
Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.