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      Cohesin phosphorylation and mobility of SMC1 at ionizing radiation-induced DNA double-strand breaks in human cells

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          Abstract

          Cohesin, a hetero-tetrameric complex of SMC1, SMC3, Rad21 and Scc3, associates with chromatin after mitosis and holds sister chromatids together following DNA replication. Following DNA damage, cohesin accumulates at and promotes the repair of DNA double-strand breaks. In addition, phosphorylation of the SMC1/3 subunits contributes to DNA damage-induced cell cycle checkpoint regulation. The aim of this study was to determine the regulation and consequences of SMC1/3 phosphorylation as part of the cohesin complex. We show here that the ATM-dependent phosphorylation of SMC1 and SMC3 is mediated by H2AX, 53BP1 and MDC1. Depletion of RAD21 abolishes these phosphorylations, indicating that only the fully assembled complex is phosphorylated. Comparison of wild type SMC1 and SMC1S966A in fluorescence recovery after photo-bleaching experiments shows that phosphorylation of SMC1 is required for an increased mobility after DNA damage in G2-phase cells, suggesting that ATM-dependent phosphorylation facilitates mobilization of the cohesin complex after DNA damage.

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          Cohesins: chromosomal proteins that prevent premature separation of sister chromatids.

          Christine Michaelis, Rafal Ciosk, Kim Nasmyth (1997)
          Cohesion between sister chromatids opposes the splitting force exerted by microtubules, and loss of this cohesion is responsible for the subsequent separation of sister chromatids during anaphase. We describe three chromosmal proteins that prevent premature separation of sister chromatids in yeast. Two, Smc1p and Smc3p, are members of the SMC family, which are putative ATPases with coiled-coil domains. A third protein, which we call Scc1p, binds to chromosomes during S phase, dissociates from them at the metaphase-to-anaphase transition, and is degraded by the anaphase promoting complex. Association of Scc1p with chromatin depends on Smc1p. Proteins homologous to Scc1p exist in a variety of eukaryotic organisms including humans. A common cohesion apparatus might be used by all eukaryotic cells during both mitosis and meiosis.
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            MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks.

            Manuel Stucki, Julie A. Clapperton, Duaa Mohammad … (2005)
            Histone variant H2AX phosphorylation in response to DNA damage is the major signal for recruitment of DNA-damage-response proteins to regions of damaged chromatin. Loss of H2AX causes radiosensitivity, genome instability, and DNA double-strand-break repair defects, yet the mechanisms underlying these phenotypes remain obscure. Here, we demonstrate that mammalian MDC1/NFBD1 directly binds to phospho-H2AX (gammaH2AX) by specifically interacting with the phosphoepitope at the gammaH2AX carboxyl terminus. Moreover, through a combination of biochemical, cell-biological, and X-ray crystallographic approaches, we reveal the molecular details of the MDC1/NFBD1-gammaH2AX complex. These data provide compelling evidence that the MDC1/NFBD1 BRCT repeat domain is the major mediator of gammaH2AX recognition following DNA damage. We further show that MDC1/NFBD1-gammaH2AX complex formation regulates H2AX phosphorylation and is required for normal radioresistance and efficient accumulation of DNA-damage-response proteins on damaged chromatin. Thus, binding of MDC1/NFBD1 to gammaH2AX plays a central role in the mammalian response to DNA damage.
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              MDC1 is a mediator of the mammalian DNA damage checkpoint.

              Grant S Stewart, Bin Wang, Colin Bignell … (2003)
              To counteract the continuous exposure of cells to agents that damage DNA, cells have evolved complex regulatory networks called checkpoints to sense DNA damage and coordinate DNA replication, cell-cycle arrest and DNA repair. It has recently been shown that the histone H2A variant H2AX specifically controls the recruitment of DNA repair proteins to the sites of DNA damage. Here we identify a novel BRCA1 carboxy-terminal (BRCT) and forkhead-associated (FHA) domain-containing protein, MDC1 (mediator of DNA damage checkpoint protein 1), which works with H2AX to promote recruitment of repair proteins to the sites of DNA breaks and which, in addition, controls damage-induced cell-cycle arrest checkpoints. MDC1 forms foci that co-localize extensively with gamma-H2AX foci within minutes after exposure to ionizing radiation. H2AX is required for MDC1 foci formation, and MDC1 forms complexes with phosphorylated H2AX. Furthermore, this interaction is phosphorylation dependent as peptides containing the phosphorylated site on H2AX bind MDC1 in a phosphorylation-dependent manner. We have shown by using small interfering RNA (siRNA) that cells lacking MDC1 are sensitive to ionizing radiation, and that MDC1 controls the formation of damage-induced 53BP1, BRCA1 and MRN foci, in part by promoting efficient H2AX phosphorylation. In addition, cells lacking MDC1 also fail to activate the intra-S phase and G2/M phase cell-cycle checkpoints properly after exposure to ionizing radiation, which was associated with an inability to regulate Chk1 properly. These results highlight a crucial role for MDC1 in mediating transduction of the DNA damage signal.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Exp Cell Res
                Journal ID (iso-abbrev): Exp. Cell Res
                Title: Experimental Cell Research
                Publisher: Academic Press
                ISSN (Print): 0014-4827
                ISSN (Electronic): 1090-2422
                Publication date PMC-release: 01 February 2011
                Publication date (Print): 01 February 2011
                Volume: 317
                Issue: 3
                Pages: 330-337
                Affiliations
                [a ]CRUK/MRC Gray Institute for Radiation Oncology & Biology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Headington, Oxford, OX3 7DQ, UK
                [b ]Health Protection Agency Centre for Radiation, Chemical and Environmental Hazards, Chilton, OX11 0RQ, UK
                [c ]Department of Genetics Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden
                Author notes
                [* ]Corresponding authors. C. Bauerschmidt and T. Helleday are to be contacted at Gray Institute for Radiation Oncology & Biology, Old Road Campus Research Building, Off Roosevelt Drive, Headington, Oxford, OX3 7DQ, UK. Fax: +44 1865 617 334. K. Rothkamm, present address: Health Protection Agency, Centre for Radiation, Chemical & Environmental Hazards, Chilton, Oxfordshire, OX11 0RQ, UK. Fax: +44 1235 833891. christina.bauerschmidt@ 123456rob.ox.ac.uk Kai.Rothkamm@ 123456hpa.org.uk thomas.helleday@ 123456rob.ox.ac.uk
                Article
                Publisher ID: YEXCR8608
                DOI: 10.1016/j.yexcr.2010.10.021
                PMC ID: 3087432
                PubMed ID: 21056556
                SO-VID: 2d0d0fd5-c48d-45c3-b46a-b5cb7446b6bd
                Copyright © © 2011 Elsevier Inc.
                License:

                This document may be redistributed and reused, subject to certain conditions.

                History
                Date received : 30 June 2010
                Date revision received : 6 October 2010
                Date accepted : 27 October 2010
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Cell biology
                Keywords: ionizing radiation,cohesin,atm,smc3,smc1,dna repair
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: ionizing radiation, cohesin, atm, smc3, smc1, dna repair

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