BMB Section Seminar: "Arginine methylation: A new player in cancer stem cells and the DNA damage response"
Dr. Clare C Davies, Birmingham Fellow and MRC New Investigator, Arginine Methylation and Gene Regulation Laboratory, Insitute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, UK
Clare C. Davies (Photo: Private)
Protein post-translational modifications expand the functional diversity of the proteome enabling dynamic modulation of cellular processes. Arginine methylation, catalysed by protein arginine methyltransferases (PRMTs), despite being identified more than 45 years ago, is a poorly characterised modification that has recently been implicated as a major regulator of tumourigenic pathways. This is particularly true for PRMT5, the main symmetric methyltransferase, which has been increasingly associated with malignant progression, particularly within the breast. Consequently, small molecule inhibitors targeting PRMT5 are in preclinical development generating notable responses in murine cancer models. However, somewhat paradoxically, we and others have found that PRMT5 is required for maintaining genome stability, a potent tumour suppressor pathway. Together, this implies that the role of PRMT5 during tumourigenesis is more complex than originally thought.
We have recently identified the AAA+ ATPase RUVBL1 as a novel PRMT5 substrate, and demonstrated that PRMT-mediated methylation of RUVBL1 promotes homologous recombination-mediated double strand break repair (Clarke et al, Molecular Cell, 2017), thereby maintaining genome stability. Mechanistically, methyl-RUVBL1 facilitates TIP60-mediated H4K16 acetylation and 53BP1 removal from double strand break ends. We have also identified a critical role for PRMT5 in the maintenance of breast cancer stem cell (BCSC) proliferation and self-renewal that has real clinical tractability because depletion of PRMT5 in established tumours significantly reduces cancer stem cell number. In this seminar, I will discuss this work, and the implications of targeting arginine methylation in the treatment of breast cancers, and our attempts in understanding the cellular mechanisms by which PRMT5 exerts its effects in health and disease.
For more info visit Clare Davies webpage