PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination

Thomas L Clarke, Maria Pilar Sanchez-Bailon, Kelly Chiang, John J Reynolds, Joaquin Herrero-Ruiz, Tiago M Bandeiras, Pedro M Matias, Sarah L Maslen, J Mark Skehel, Grant S Stewart, Clare C Davies

Research output: Contribution to journalArticlepeer-review


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 mobilization 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 localization.

Original languageEnglish
Pages (from-to)900-916.e7
Number of pages25
JournalMolecular Cell
Issue number5
Early online date23 Feb 2017
Publication statusPublished - 2 Mar 2017


  • ATPases Associated with Diverse Cellular Activities
  • Acetylation
  • Animals
  • Arginine
  • Ataxia Telangiectasia Mutated Proteins/metabolism
  • Carrier Proteins/genetics
  • DNA Breaks, Double-Stranded
  • DNA Helicases/genetics
  • Genomic Instability
  • HEK293 Cells
  • HeLa Cells
  • Histone Acetyltransferases/genetics
  • Histones/metabolism
  • Humans
  • Lysine Acetyltransferase 5
  • Methylation
  • Mice
  • Mice, Transgenic
  • Protein Processing, Post-Translational
  • Protein-Arginine N-Methyltransferases/genetics
  • RNA Interference
  • Recombinational DNA Repair
  • Time Factors
  • Transfection
  • Tumor Suppressor p53-Binding Protein 1/genetics


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