title: Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining.
abstract: Given its significant role in the maintenance of genomic stability, histone methylation has been postulated to regulate DNA repair. Histone methylation mediates localization of 53BP1 to a DNA double-strand break (DSB) during homologous recombination repair, but a role in DSB repair by nonhomologous end-joining (NHEJ) has not been defined. By screening for histone methylation after DSB induction by ionizing radiation we found that generation of dimethyl histone H3 lysine 36 (H3K36me2) was the major event. Using a novel human cell system that rapidly generates a single defined DSB in the vast majority of cells, we found that the DNA repair protein Metnase (also SETMAR), which has a SET histone methylase domain, localized to an induced DSB and directly mediated the formation of H3K36me2 near the induced DSB. This dimethylation of H3K36 improved the association of early DNA repair components, including NBS1 and Ku70, with the induced DSB, and enhanced DSB repair. In addition, expression of JHDM1a (an H3K36me2 demethylase) or histone H3 in which K36 was mutated to A36 or R36 to prevent H3K36me2 formation decreased the association of early NHEJ repair components with an induced DSB and decreased DSB repair. Thus, these experiments define a histone methylation event that enhances DNA DSB repair by NHEJ.
authors.affiliation: University of New Mexico Cancer Center and Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
authors.forename: Sheema
authors.initials: S
authors.lastname: Fnu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Williamson
authors.forename: Leyma P
authors.initials: LP
authors.lastname: De Haro
authors.forename: Mark
authors.initials: M
authors.lastname: Brenneman
authors.forename: Justin
authors.initials: J
authors.lastname: Wray
authors.forename: Montaser
authors.initials: M
authors.lastname: Shaheen
authors.forename: Krishnan
authors.initials: K
authors.lastname: Radhakrishnan
authors.forename: Suk-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Jac A
authors.initials: JA
authors.lastname: Nickoloff
authors.forename: Robert
authors.initials: R
authors.lastname: Hromas
mesh_terms: D034961:Antigens, Nuclear / Q000737:chemistry; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D019175:DNA Methylation; D004260:DNA Repair; D004262:DNA Restriction Enzymes / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000737:chemistry; D015252:Deoxyribonucleases, Type II Site-Specific / Q000494:pharmacology; D019281:Dimerization; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000737:chemistry*; D006801:Humans; D000072200:Ku Autoantigen; D008239:Lysine / Q000737:chemistry*; D008962:Models, Theoretical; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins / Q000494:pharmacology; D013997:Time Factors
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D006657:Histones; D029701:Saccharomyces cerevisiae Proteins; D011495:Histone-Lysine N-Methyltransferase; C510450:SETMAR protein, human; D004262:DNA Restriction Enzymes; C037725:SCEI protein, S cerevisiae; D015252:Deoxyribonucleases, Type II Site-Specific; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; D008239:Lysine