title: PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination.
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.
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Clarke
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Maria Pilar
authors.initials: MP
authors.lastname: Sanchez-Bailon
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chiang
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Reynolds
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Herrero-Ruiz
authors.affiliation: Instituto de Biologia Experimental e Tecnológica, 2780-157 Oeiras, Portugal.
authors.forename: Tiago M
authors.initials: TM
authors.lastname: Bandeiras
authors.affiliation: Instituto de Biologia Experimental e Tecnológica, 2780-157 Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Matias
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Maslen
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Skehel
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Grant S
authors.initials: GS
authors.lastname: Stewart
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: c.c.davies@bham.ac.uk.
authors.forename: Clare C
authors.initials: CC
authors.lastname: Davies
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000107:Acetylation; D000818:Animals; D001120:Arginine; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability; D057809:HEK293 Cells; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D059767:Recombinational DNA Repair; D013997:Time Factors; D014162:Transfection; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D006657:Histones; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D001120:Arginine; C400529:PRMT5 protein, human; C498518:Prmt5 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C486549:RUVBL1 protein, human
keywords: 52BP1; DNA repair; PRMT5; RUVBL1; TIP60; arginine methylation; homologous recombination