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

Mol Cell. 2017 Mar 2;65(5):900-916.e7. doi: 10.1016/j.molcel.2017.01.019. Epub 2017 Feb 23.

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 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.

Keywords: 52BP1; DNA repair; PRMT5; RUVBL1; TIP60; arginine methylation; homologous recombination.

MeSH terms

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

Substances

  • Carrier Proteins
  • Histones
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Arginine
  • PRMT5 protein, human
  • Prmt5 protein, mouse
  • Protein-Arginine N-Methyltransferases
  • Histone Acetyltransferases
  • KAT5 protein, human
  • Lysine Acetyltransferase 5
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • ATPases Associated with Diverse Cellular Activities
  • DNA Helicases
  • RUVBL1 protein, human