PRMT5-dependent methylation of the TIP60 coactivator RUVBL1 is a key regulator of homologous recombination

Research output: Contribution to journalArticle

Colleges, School and Institutes

Abstract

Protein post-translation modification plays an important role in regulating DNA repair, however the role of arginine methylation in this process is poorly understood. Here, we identify the arginine methyltransferase, PRMT5 as a key regulator of homologous recombination (HR)-mediated double strand break (DSB) repair, which is mediated through its ability to methylate RUVBL1, a cofactor of the TIP60 complex. We show that PRMT5 targets RUVBL1 for methylation at position R205, which facilitates TIP60-dependent mobilisation of 53BP1 from DNA breaks, promoting HR. Mechanistically, we demonstrate that PRMT5-directed methylation of RUVBL1 is critically required for the acetyltransferase activity of TIP60, promoting histone H4K16 acetylation, which facilities 53BP1 displacement from DSBs. Interestingly, RUVBL1 methylation did not affect the ability of TIP60 to facilitate ATM activation. Taken together, our findings reveal the importance of PRMT5-mediated arginine methylation during DSB repair pathway choice through its ability to regulate acetylation-dependent control of 53BP1 localisation.

Details

Original languageEnglish
Pages (from-to)900–916.e7
JournalMolecular Cell
Volume65
Issue number2
Early online date23 Feb 2017
Publication statusPublished - 2 Mar 2017

Keywords

  • PRMT5, RUVBL1, DNA repair, arginine methylation, 53BP1