PRMT5 promotes chemoresistance of breast cancer stem cells by regulating DNA repair gene splicing facilitating an enhanced DNA damage response

Breast cancer stem cells (BCSCs) are a rare cell population that are responsible for tumour initiation, metastasis, chemoresistance and tumour relapse. 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 modulation of DNA repair efficiency. Notably, PRMT5 inhibitors synergise with cisplatin and radiotherapy, inducing defective DNA repair thereby potentiating BCSC apoptosis. Mechanistically, we demonstrate the crucial function of PRMT5 in ensuring splicing fidelity of DNA damage response genes, particularly those integral to the Fanconi Anaemia and homologous recombination pathways. A comparison of BCSCs and their bulk cell progeny identified shared (ATM, DDX11, EXO1, FAN1, SLX4) and unique (ATR, RAD17, RAD51D, RUVBL1) PRMT5-dependent alternative splicing events. Surprisingly, these events rarely repressed gene expression, suggesting that PRMT5 inhibition predominantly results in nuclear detention of intron-containing transcripts and the production of non-canonical isoforms with compromised protein function. This study thus reveals promising strategies to improve the therapeutic efficacy of PRMT5 inhibitors that promote effective BCSC eradication.