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Critical Roles of Ring Finger Protein RNF8 in Replication Stress Responses*

  • Shirley M.-H. Sy
    Footnotes
    Affiliations
    Genome Stability Research Laboratory, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China

    Department of Anatomy, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China

    Centre for Cancer Research, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China
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  • Jun Jiang
    Footnotes
    Affiliations
    College of Life Sciences, South China Agricultural University, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China
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  • Sui-sui Dong
    Affiliations
    Genome Stability Research Laboratory, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China

    Department of Anatomy, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China

    Centre for Cancer Research, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China
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  • Gabriel Tsz Mei Lok
    Affiliations
    Genome Stability Research Laboratory, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China

    Department of Anatomy, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China

    Centre for Cancer Research, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China
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  • Jun Wu
    Affiliations
    College of Life Sciences, South China Agricultural University, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China
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  • Hua Cai
    Affiliations
    College of Life Sciences, South China Agricultural University, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China
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  • Enoch S.L. Yeung
    Affiliations
    Genome Stability Research Laboratory, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China

    Department of Anatomy, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China
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  • Jun Huang
    Affiliations
    Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China
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  • Junjie Chen
    Affiliations
    Department of Experimental Radiation Oncology, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
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  • Yiqun Deng
    Correspondence
    To whom correspondence may be addressed
    Affiliations
    College of Life Sciences, South China Agricultural University, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China
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  • Michael S.Y. Huen
    Correspondence
    To whom correspondence may be addressed
    Affiliations
    Genome Stability Research Laboratory, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China

    Department of Anatomy, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China

    Centre for Cancer Research, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong, China
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  • Author Footnotes
    * This work was supported by the Faculty Development Fund and Seed Funding Programme for Applied Research (Project Code 201007160001, to M. S. Y. H.), by grants from the National Basic Research Program of China (973 Program, Grant 2009CB118802, to M. S. Y. H. and Y. D.), and by Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2009, to Y. D.).
    The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S6.
    1 Both authors contributed equally to this work.
Open AccessPublished:May 10, 2011DOI:https://doi.org/10.1074/jbc.M111.232041
      Histone ubiquitylation is emerging as an important protective component in cellular responses to DNA damage. The ubiquitin ligases RNF8 and RNF168 assemble ubiquitin chains onto histone molecules surrounding DNA breaks and facilitate retention of DNA repair proteins. Although RNF8 and RNF168 play important roles in repair of DNA double strand breaks, their requirement for cell protection from replication stress is largely unknown. In this study, we uncovered RNF168-independent roles of RNF8 in repair of replication inhibition-induced DNA damage. We showed that RNF8 depletion, but not RNF168 depletion, hyper-sensitized cells to hydroxyurea and aphidicolin treatment. Consistently, hydroxyurea induced persistent single strand DNA lesions and sustained CHK1 activation in RNF8-depleted cells. In line with strict requirement for RAD51-dependent repair of hydroxyurea-stalled replication forks, RNF8 depletion compromised RAD51 accumulation onto single strand DNA lesions, suggesting that impaired replication fork repair may underlie the enhanced cellular sensitivity to replication arrest observed in RNF8-depleted cells. In total, our study highlights the differential requirement for the ubiquitin ligase RNF8 in facilitating repair of replication stress-associated DNA damage.

      Introduction

      The ubiquitin-dependent DNA-damage signaling cascade involving the E3
      The abbreviations used are: E3
      ubiquitin-protein isopeptide ligase
      HR
      homologous recombination
      NHEJ
      non-homologous end-joining
      HU
      hydroxyurea
      ssDNA
      single strand DNA
      RPA
      replication protein A.
      ubiquitin ligases RNF8 and RNF168 plays key roles in coordinating cell cycle progression and DNA repair (
      • Marteijn J.A.
      • Bekker-Jensen S.
      • Mailand N.
      • Lans H.
      • Schwertman P.
      • Gourdin A.M.
      • Dantuma N.P.
      • Lukas J.
      • Vermeulen W.
      ,
      • Huen M.S.
      • Grant R.
      • Manke I.
      • Minn K.
      • Yu X.
      • Yaffe M.B.
      • Chen J.
      ,
      • Kolas N.K.
      • Chapman J.R.
      • Nakada S.
      • Ylanko J.
      • Chahwan R.
      • Sweeney F.D.
      • Panier S.
      • Mendez M.
      • Wildenhain J.
      • Thomson T.M.
      • Pelletier L.
      • Jackson S.P.
      • Durocher D.
      ,
      • Mailand N.
      • Bekker-Jensen S.
      • Faustrup H.
      • Melander F.
      • Bartek J.
      • Lukas C.
      • Lukas J.
      ,
      • Wang B.
      • Elledge S.J.
      ,
      • Doil C.
      • Mailand N.
      • Bekker-Jensen S.
      • Menard P.
      • Larsen D.H.
      • Pepperkok R.
      • Ellenberg J.
      • Panier S.
      • Durocher D.
      • Bartek J.
      • Lukas J.
      • Lukas C.
      ,
      • Pinato S.
      • Scandiuzzi C.
      • Arnaudo N.
      • Citterio E.
      • Gaudino G.
      • Penengo L.
      ,
      • Stewart G.S.
      • Panier S.
      • Townsend K.
      • Al-Hakim A.K.
      • Kolas N.K.
      • Miller E.S.
      • Nakada S.
      • Ylanko J.
      • Olivarius S.
      • Mendez M.
      • Oldreive C.
      • Wildenhain J.
      • Tagliaferro A.
      • Pelletier L.
      • Taubenheim N.
      • Durandy A.
      • Byrd P.J.
      • Stankovic T.
      • Taylor A.M.
      • Durocher D.
      ). Dysregulation of this cascade contributes to genome instability and tumorigenesis (
      • Li L.
      • Halaby M.J.
      • Hakem A.
      • Cardoso R.
      • El Ghamrasni S.
      • Harding S.
      • Chan N.
      • Bristow R.
      • Sanchez O.
      • Durocher D.
      • Hakem R.
      ,
      • Stewart G.S.
      • Stankovic T.
      • Byrd P.J.
      • Wechsler T.
      • Miller E.S.
      • Huissoon A.
      • Drayson M.T.
      • West S.C.
      • Elledge S.J.
      • Taylor A.M.
      ). Current evidence suggests that, in concert with the E2-conjugating enzyme UBC13, RNF168 amplifies the RNF8-initiated DNA-damage signal, in part, by extending non-degradative Lys63-linked ubiquitin chains on H2A-type histone molecules. Ubiquitylated histones then serve as recruiting factors to promote productive assembly of checkpoint and repair proteins, including 53BP1, RAD18, and BRCA1, to the damaged-modified chromatin (
      • Huen M.S.
      • Chen J.
      ). However, despite the mechanistic details that ascribed crucial roles of the RNF8-RNF168 module for cell survival from ionizing radiation-induced DNA double strand breaks and for class-switch recombination (
      • Li L.
      • Halaby M.J.
      • Hakem A.
      • Cardoso R.
      • El Ghamrasni S.
      • Harding S.
      • Chan N.
      • Bristow R.
      • Sanchez O.
      • Durocher D.
      • Hakem R.
      ,
      • Noon A.T.
      • Shibata A.
      • Rief N.
      • Löbrich M.
      • Stewart G.S.
      • Jeggo P.A.
      • Goodarzi A.A.
      ,
      • Ramachandran S.
      • Chahwan R.
      • Nepal R.M.
      • Frieder D.
      • Panier S.
      • Roa S.
      • Zaheen A.
      • Durocher D.
      • Scharff M.D.
      • Martin A.
      ,
      • Santos M.A.
      • Huen M.S.
      • Jankovic M.
      • Chen H.T.
      • López-Contreras A.J.
      • Klein I.A.
      • Wong N.
      • Barbancho J.L.
      • Fernandez-Capetillo O.
      • Nussenzweig M.C.
      • Chen J.
      • Nussenzweig A.
      ), it remains largely unknown whether the ubiquitin ligases are similarly required for repair of other types of DNA lesions.
      Homologous recombination (HR) DNA repair factors play crucial roles following replication arrest in mammalian cells. Previous work indicated that HR-deficient cells, but not non-homologous end-joining (NHEJ)-defective cells, are especially sensitive to agents that induce replication fork stalling (
      • Lundin C.
      • Erixon K.
      • Arnaudeau C.
      • Schultz N.
      • Jenssen D.
      • Meuth M.
      • Helleday T.
      ). Moreover, cells that overexpress the HR recombinase RAD51-rendered cells resistant to replication inhibitors, including hydroxyurea (HU) and thymidine (
      • Lundin C.
      • Schultz N.
      • Arnaudeau C.
      • Mohindra A.
      • Hansen L.T.
      • Helleday T.
      ), suggesting that HR-repair proteins play a predominant role in promoting repair/restart of damaged replication forks. Interestingly, the E3 ubiquitin ligase RNF8 has been implicated in efficient HR DNA repair, in part, via the RAD18-RAD51C axis (
      • Huang J.
      • Huen M.S.
      • Kim H.
      • Leung C.C.
      • Glover J.N.
      • Yu X.
      • Chen J.
      ). Accordingly, RNF8 deficiency compromised RAD51 focal accumulation at IR-induced DNA breaks, and these cells exhibited impaired HR as determined using the mutant GFP gene conversion assay. By contrast, cells deficient in RNF168 displayed enhanced RAD51 foci formation in response to IR (
      • Stewart G.S.
      • Stankovic T.
      • Byrd P.J.
      • Wechsler T.
      • Miller E.S.
      • Huissoon A.
      • Drayson M.T.
      • West S.C.
      • Elledge S.J.
      • Taylor A.M.
      ). More strikingly, whereas RNF8 is essential in IR-induced foci formation of RAD18, BRCA1, and 53BP1, RNF168-deficient cells supported double strand break association of RAD18 and BRCA1 at later time points after IR treatment (
      • Stewart G.S.
      • Panier S.
      • Townsend K.
      • Al-Hakim A.K.
      • Kolas N.K.
      • Miller E.S.
      • Nakada S.
      • Ylanko J.
      • Olivarius S.
      • Mendez M.
      • Oldreive C.
      • Wildenhain J.
      • Tagliaferro A.
      • Pelletier L.
      • Taubenheim N.
      • Durandy A.
      • Byrd P.J.
      • Stankovic T.
      • Taylor A.M.
      • Durocher D.
      ,
      • Stewart G.S.
      • Stankovic T.
      • Byrd P.J.
      • Wechsler T.
      • Miller E.S.
      • Huissoon A.
      • Drayson M.T.
      • West S.C.
      • Elledge S.J.
      • Taylor A.M.
      ) (supplemental Fig. S1). Together, these data suggest that there may be functional differences between RNF8 and RNF168 in cellular responses to DNA damage.

      DISCUSSION

      RNF8 and RNF168 ubiquitin ligases orchestrate DNA-damage responses via a non-canonical ubiquitin-dependent signaling pathway (
      • Panier S.
      • Durocher D.
      ). Specifically, RNF8-RNF168 catalyze histone ubiquitylation at chromatin domains flanking a DNA-damage site, facilitate the accumulation of checkpoint and repair factors, and promote DNA repair and cell survival. In contrast to their similar functional requirement for IR-induced or programmed double strand break repair (
      • Huen M.S.
      • Grant R.
      • Manke I.
      • Minn K.
      • Yu X.
      • Yaffe M.B.
      • Chen J.
      ,
      • Kolas N.K.
      • Chapman J.R.
      • Nakada S.
      • Ylanko J.
      • Chahwan R.
      • Sweeney F.D.
      • Panier S.
      • Mendez M.
      • Wildenhain J.
      • Thomson T.M.
      • Pelletier L.
      • Jackson S.P.
      • Durocher D.
      ,
      • Mailand N.
      • Bekker-Jensen S.
      • Faustrup H.
      • Melander F.
      • Bartek J.
      • Lukas C.
      • Lukas J.
      ,
      • Wang B.
      • Elledge S.J.
      ,
      • Doil C.
      • Mailand N.
      • Bekker-Jensen S.
      • Menard P.
      • Larsen D.H.
      • Pepperkok R.
      • Ellenberg J.
      • Panier S.
      • Durocher D.
      • Bartek J.
      • Lukas J.
      • Lukas C.
      ,
      • Pinato S.
      • Scandiuzzi C.
      • Arnaudo N.
      • Citterio E.
      • Gaudino G.
      • Penengo L.
      ,
      • Stewart G.S.
      • Panier S.
      • Townsend K.
      • Al-Hakim A.K.
      • Kolas N.K.
      • Miller E.S.
      • Nakada S.
      • Ylanko J.
      • Olivarius S.
      • Mendez M.
      • Oldreive C.
      • Wildenhain J.
      • Tagliaferro A.
      • Pelletier L.
      • Taubenheim N.
      • Durandy A.
      • Byrd P.J.
      • Stankovic T.
      • Taylor A.M.
      • Durocher D.
      ,
      • Li L.
      • Halaby M.J.
      • Hakem A.
      • Cardoso R.
      • El Ghamrasni S.
      • Harding S.
      • Chan N.
      • Bristow R.
      • Sanchez O.
      • Durocher D.
      • Hakem R.
      ,
      • Noon A.T.
      • Shibata A.
      • Rief N.
      • Löbrich M.
      • Stewart G.S.
      • Jeggo P.A.
      • Goodarzi A.A.
      ,
      • Ramachandran S.
      • Chahwan R.
      • Nepal R.M.
      • Frieder D.
      • Panier S.
      • Roa S.
      • Zaheen A.
      • Durocher D.
      • Scharff M.D.
      • Martin A.
      ,
      • Santos M.A.
      • Huen M.S.
      • Jankovic M.
      • Chen H.T.
      • López-Contreras A.J.
      • Klein I.A.
      • Wong N.
      • Barbancho J.L.
      • Fernandez-Capetillo O.
      • Nussenzweig M.C.
      • Chen J.
      • Nussenzweig A.
      ), our study uncovered a specific requirement for RNF8, but not RNF168, in the repair of replication-associated DNA damage. We found that, in response to HU treatment, RNF8 promoted RAD51-dependent repair of damaged replication forks, dysregulation of which resulted in sustained DNA damage, prolonged G2 arrest, and compromised cell survival.
      Exposure of ssDNA lesions results in accumulation and subsequent phosphorylation of RPA complexes, which in turn signals for assimilation of the recombinase RAD51 onto ssDNAs. Our observation, that both RPA and CHK1 phosphorylation persisted in RNF8-depleted cells, is suggestive of defective DNA repair in these cells. Previous studies have implicated homologous recombination DNA repair factors, including RAD51, in repair and restart of damaged replication forks. Consistently, we found that RAD51 accumulation to HU-induced RPA-coated DNA lesions was impaired in RNF8-, but not RNF168-depleted cells, suggesting that RNF8 promotes RAD51-dependent repair and/or restart of damaged replication forks. Although we propose that RNF168 is largely dispensable for cell survival following replication inhibition, it is noteworthy to mention that proper RAD18 accumulation at DNA-damage sites requires the concerted actions of RNF8 and RNF168 (supplemental Fig. S1). Interestingly, we found that RNF168-deficient RIDDLE cells, unlike those with RNF8 deficiency, supported RAD18 foci formation 24 h post IR treatment. Our observation that RAD18, in the absence of RNF168, is recruited to DNA-damage sites with reduced kinetics implies that RNF8 catalyzes “limiting” amounts of ubiquitin conjugates, which over time accumulates to levels such that microscopically visible RAD18 foci become detectable. Although it remains to be seen whether mono-ubiquitylated H2A-type histones are responsible for tethering RAD18 to the vicinity of DNA lesions (Fig. 1e), given the fact that both RAD18 and its ability to associate at RNF8-dependent ubiquitin structures were pivotal in promoting cell survival in response to HU treatment, and that RNF8 and RAD18 are epistatic in cellular response to genotoxic stress, we speculate that RNF8 promotes replication fork repair by concentrating repair factors, including RAD18 and RAD51, at HU-induced ssDNA lesions.
      Interestingly, our observation indicated that levels of damage-induced, RNF8-dependent H2AX mono-ubiquitylation were significantly reduced in cells depleted of RNF168. This observation can be explained by roles of RNF168 in amplifying the ubiquitin-dependent DNA-damage signals at the vicinity of DNA breaks. Apart from “extending” the RNF8-primed histone ubiquitylation via K63-linked poly-ubiquitylation, docking of RNF168 to the RNF8-primed ubiquitylated H2A-type histones may allow it to “spread” DNA-damage signals by mono-ubiquitylating adjacent histone molecules. In support of the possibility that both RNF8 and RNF168 may promote H2AX mono-ubiquitylation, a previous study indicated that co-depletion of both E3 ubiquitin ligases is essential to inhibit the ATM-mediated gene silencing effect near a DNA double strand break (
      • Shanbhag N.M.
      • Rafalska-Metcalf I.U.
      • Balane-Bolivar C.
      • Janicki S.M.
      • Greenberg R.A.
      ). Further experiments will be needed to understand the RNF8- and RNF168-catalyzed ubiquitin conjugates and their topologies at sites of DNA damage.
      In summary, our study uncovered distinct and strict requirement for RNF8 in cell recovery following replication arrest. Notably, we found that RNF8 alone was sufficient in promoting timely repair of HU-induced DNA damage, in part, via RAD51-dependent replication fork repair. Given the dynamic nature and the complexity of histone ubiquitylation at sites of DNA breaks, it remains to be seen whether and how ubiquitin signals may have evolved with more sophisticated and specific tasks in the maintenance of genome stability.

      Acknowledgments

      M. S. Y. H. thanks Dr. X. Yu for antibodies, Dr. G. Stewart for RIDDLE cells, and the Faculty Core Imaging Facility for use of fluorescence microscopy.

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