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Methylation of Histone H3 Lysine 36 Enhances DNA Repair by Nonhomologous End-Joining

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Methylation of Histone H3 Lysine 36 Enhances DNA Repair by Nonhomologous End-Joining Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining Sheema Fnua, Elizabeth A. Williamsona, Leyma P. De Haroa, Mark Brennemanb, Justin Wraya, Montaser Shaheena, Krishnan Radhakrishnana, Suk-Hee Leec, Jac A. Nickoloffd,1, and Robert Hromasa,1 aUniversity of New Mexico Cancer Center and Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; bDepartment of Genetics, Rutgers University, Piscataway, NJ 08854; cDepartment of Biochemistry and Molecular Biology, Indiana University Medical Center, Indianapolis, IN 46202; and dDepartment of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523 Edited by Richard D. Kolodner, Ludwig Institute for Cancer Research, La Jolla, CA, and approved November 22, 2010 (received for review September 9, 2010) Given its significant role in the maintenance of genomic stability, (10). Because H3K36me2 is the major histone dimethylation histone methylation has been postulated to regulate DNA repair. event induced by the formation of DSBs, and Metnase enhances Histone methylation mediates localization of 53BP1 to a DNA dou- DSB repair, we hypothesized that the SET domain of Metnase ble-strand break (DSB) during homologous recombination repair, mediated this histone methylation event. Because the SET do- but a role in DSB repair by nonhomologous end-joining (NHEJ) main of Metnase was required for its ability to enhance NHEJ has not been defined. By screening for histone methylation after DSB repair, we investigated whether Metnase directly methylated DSB induction by ionizing radiation we found that generation of H3K36 at a DSB and how this histone methylation event func- dimethyl histone H3 lysine 36 (H3K36me2) was the major event. tioned in DSB repair by NHEJ. Toanswer these questions, we gen- Using a novel human cell system that rapidly generates a single erated a human cell system in which a single DSB is rapidly and defined DSB in the vast majority of cells, we found that the DNA synchronously induced in a defined sequence and this DSB is pre- repair protein Metnase (also SETMAR), which has a SET histone ferentially repaired by NHEJ. This unique cell system provided methylase domain, localized to an induced DSB and directly the template for analysis of repair protein recruitment to the DSB, mediated the formation of H3K36me2 near the induced DSB. This and histone modification at that site, using chromatin immuno- dimethylation of H3K36 improved the association of early DNA re- precipitation. We found that (i) Metnase directly mediated the BIOCHEMISTRY pair components, including NBS1 and Ku70, with the induced DSB, formation of H3K36me2 at the induced DSB, (ii) H3K36me2 and enhanced DSB repair. In addition, expression of JHDM1a (an recruited and stabilized other DNA repair components at the H3K36me2 demethylase) or histone H3 in which K36 was mutated DSB, and (iii) H3K36me2 levels were proportional to DSB repair to A36 or R36 to prevent H3K36me2 formation decreased the as- efficiency. sociation of early NHEJ repair components with an induced DSB and decreased DSB repair. Thus, these experiments define a histone Results methylation event that enhances DNA DSB repair by NHEJ. Histone H3 Lysine 36 is Dimethylated at DSBs. We screened H3 for the induction of dimethylation events after DSB induction with double-strand break ∣ I-Sce-I ∣ chromatin immunoprecipitation ∣ IR or etoposide using Western analysis. We found that of the MRN complex ∣ mathematical modeling methylation events assessed, H3K36me2 was the major event, and was rapidly induced after IR (Fig. 1A and Fig. S1). This his- istone methylation is highly regulated by a family of proteins tone modification is a general response to DSB formation because Htermed histone methylases, which usually share a SET do- H3K36me2 was induced by IR to some extent in eight of eight cell main (1–3). Histone methylation plays a key role in chromatin lines tested (Fig. S2). However, we did not see any increase in remodeling and as such regulates transcription, replication, cell H3K36 trimethylation after IR. To test whether H3K36me2 was differentiation, genome stability, and apoptosis (1–3). Because of associated with DSB formation and repair, and whether Metnase its role in replication and genome stability, histone methylation could mediate this methylation event, we generated a model has been hypothesized to play an important role in DNA repair. human cell system in which a single DSB could be induced rapidly DNA double-strand breaks (DSBs) are a cytotoxic form of DNA and efficiently within a defined unique sequence, where this DSB damage that disrupts many of the cellular functions regulated would preferentially be repaired by NHEJ. The human sarcoma by histone methylation described above (4–6). Previous reports cell line HT1080 was engineered to contain an I-SceI site in a indicate that histone methylation may be important in DNA DSB single-copy puromycin acetyltransferase (puro) gene sequence repair by homologous recombination: The DSB repair compo- (Fig. 1 and Fig. S3). By using adenoviral-mediated transduction nent 53BP1, which is required for proper homologous recombi- of I-SceI endonuclease (15–17), DSBs were produced in 90% of nation, is recruited to sites of damage by methylated histone cells within 60 min (Fig. 1 B and C and Figs. S3 and S4). Given that H3 lysine 79 (H3K79) and histone H4 lysine 20 (H4K20) (7–9). the puro sequence is integrated as a single copy, cells experience However, neither H3K79 nor H4K20 methylation is induced by either a single DSB in one chromosome or two DSBs in sister DNA damage (9), so other histone methylation events at sites of chromatids, and these DSBs are likely to be preferentially re- DNA damage have been sought. In addition, a mechanism by which histone methylation might regulate NHEJ DSB repair has yet to be defined. In this study, a survey of histone methylation Author contributions: S.F., E.W., M.S., J.A.N., and R.A.H. designed research; S.F. and E.W. performed research; S.F., L.P.D.H., M.A.B., J.W., K.R., and S.-H.L. contributed new reagents/ events after DSB induction revealed that the major immediate analytic tools; S.F., M.A.B., J.W., M.S., K.R., S.-H.L., J.A.N., and R.A.H. analyzed data; and H3 methylation event is H3K36me2. M.A.B., S.-H.L., J.A.N., and R.A.H. wrote the paper. Metnase is a DNA DSB repair component that is a fusion of a The authors declare no conflict of interest. SET histone methylase domain with a nuclease domain and a do- This article is a PNAS Direct Submission. – main from a member of the transposase/integrase family (10 14). Freely available online through the PNAS open access option. We showed previously that Metnase enhances nonhomologous 1To whom correspondence may be addressed. E-mail: [email protected] or end-joining (NHEJ) repair of, and survival after, DNA DSBs, [email protected]. and that its SET domain was essential for this activity (10). We This article contains supporting information online at www.pnas.org/lookup/suppl/ also found that Metnase directly dimethylated H3K36 in vitro doi:10.1073/pnas.1013571108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1013571108 PNAS Early Edition ∣ 1of6 Downloaded by guest on September 28, 2021 A 8 Gy IR B q-RT PCR C126hr0.25 100 H3K36me2 H3 ) 80 Actin 60 MOI=1000 C PCR I-SceI DSBs (% 40 1 2 4 8 24 hr I-SceI 20 MOI=100 pcDNA 0 pcDNA-Metnase 0246824 42 D H3K36me2 E Metnase pcDNA 80 ** H3K4me2 50 pcDNA-Metnase H3K79me2 ** U6 ** H3K9me2 40 U6-si-Metnase 60 alues) ** ** e v 30 40 ** 20 ** 20 ** ** ** ** ** ** 10 ChIP (Relativ ** ** 0 0 ** 0246824 42 0246824 42 H3K36me2 pcDNA H3K36me2 pCAGGS F G pCAGGS-Metnase 200 pcDNA-Metnase 200 pCAGGS-Metnase D248S U6 ** ** U6-si-Metnase 150 150 ** ** ** * 100 100 ** * ** 50 50 ** ** ** ** ** ChIP (Re latvalues) ive ** * ** ** 0 0 ** ** 0246824 42 0 246824 42 Time after DSB (h) Time after DSB (h) Fig. 1. Metnase dimethylates H3K36 at DSBs. (A) Western blot of H3K36me2 after γ-radiation. (B) Quantitative real-time PCR analysis using PCR primers spanning the I-SceI site. Plotted are relative values calculated as the inverse of the total amount of amplified puro DNA compared to input GAPDH DNA for I-SceI adenovirus MOIs of 100 and 1,000. (C) Schematic of the HT1904 I-SceI DSB cell system (see also Figs. S3 and S4). (D) ChIP time course of methylated H3 species adjacent to a single induced DSB quantified by real-time PCR. Methylated H3K36 was not detected prior to DSB induction. For all ChIP and DSB repair experiments, each time point is the average of three quantitative real-time PCR measurements normalized to input DNA. All H3K36me2 ChIP data were also normalized to the presence of total H3 assessed by ChIP at the DSB. All data points include errors bars (SEM), but in many cases the error bars are smaller than data point symbols. Statistics were calculated for each time point vs. controls. In this and all subsequent figures, * indicates P ≤ 0.05 and ** indicates P ≤ 0.01. (E and F) ChIP analysis of Metnase and H3K36me2 adjacent to a single induced DSB. pcDNA-Metnase indicates Metnase overexpression, U6-si-Metnase indicates repression; pcDNA and U6 are empty vector controls. There was no detectable Metnase or H3K36me2 prior to DSB induction. (G) The Metnase D248S SET domain mutant prevents H3K36me2 formation at the DSB. paired by NHEJ. This engineered model cell system was termed each time point as well as input DNA. There was no detectable HT1904. These cells were further manipulated to over- or under- colocalization of H3K36me2 and γ-H2AX foci by confocal immu- express H3 methylase and demethylase activities.
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