SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage
Open accessAbstract
Here we demonstrate that RNF4, a highly conserved small ubiquitin-like modifier (SUMO)-targeted ubiquitin E3 ligase, plays a critical role in the response of mammalian cells to DNA damage. Human cells in which RNF4 expression was ablated by siRNA or chicken DT40 cells with a homozygous deletion of the RNF4 gene displayed increased sensitivity to DNA-damaging agents. Recruitment of RNF4 to double-strand breaks required its RING and SUMO interaction motif (SIM) domains and DNA damage factors such as NBS1, mediator of DNA damage checkpoint 1 (MDC1), RNF8, 53BP1, and BRCA1. In the absence of RNF4, these factors were still recruited to sites of DNA damage, but 53BP1, RNF8, and RNF168 displayed delayed clearance from such foci. SILAC-based proteomics of SUMO substrates revealed that MDC1 was SUMO-modified in response to ionizing radiation. As a consequence of SUMO modification, MDC1 recruited RNF4, which mediated ubiquitylation at the DNA damage site. Failure to recruit RNF4 resulted in defective loading of replication protein A (RPA) and Rad51 onto ssDNA. This appeared to be a consequence of reduced recruitment of the CtIP nuclease, resulting in inefficient end resection. Thus, RNF4 is a novel DNA damage-responsive protein that plays a role in homologous recombination and integrates SUMO modification and ubiquitin signaling in the cellular response to genotoxic stress.
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RNF4, a SUMO-targeted ubiquitin E3 ligase, is recruited to double-strand breaks by MDC1 and promotes DNA repair and the cellular response to double-strand breaks.
“RNF4, a SUMO-targeted ubiquitin E3 ligase, is recruited to DSBs by MDC1 and promotes DNA repair and cellular response to DSBs [66, 67].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [66]
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Cites
The DNA damage response: putting checkpoints in perspective
Zhou, B.-B. S., & Elledge, S. J. (2000) · Nature · doi:10.1038/35044005 · Cited by 3,213 · see citing works
A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage
Paull, T. T., Rogakou, E. P., Yamazaki, V., Kirchgessner, C. U., Gellert, M., & Bonner, W. M. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00610-2 · Cited by 2,098 · see citing works
Human CtIP promotes DNA end resection
Sartori, A. A., Lukas, C., Coates, J., Mistrik, M., Fu, S., Bartek, J., Baer, R., Lukas, J., & Jackson, S. P. (2007) · Nature · doi:10.1038/nature06337 · Cited by 1,362 · see citing works
RNF8 Ubiquitylates Histones at DNA Double-Strand Breaks and Promotes Assembly of Repair Proteins
Mailand, N., Bekker‐Jensen, S., Kildegaard, H. F., Melander, F., Bártek, J., Lukas, C., & Lukas, J. (2007) · Cell · doi:10.1016/j.cell.2007.09.040 · Cited by 1,153 · see citing works
Requirement of the MRN complex for ATM activation by DNA damage
Uziel, T., Lerenthal, Y., Moyal, L., Andegeko, Y., Mittelman, L., & Shiloh, Y. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg541 · Cited by 1,075 · see citing works
RNF8 Transduces the DNA-Damage Signal via Histone Ubiquitylation and Checkpoint Protein Assembly
Huen, M. S. Y., Grant, R. A., Manke, I. A., Minn, K. T., Yu, X., Yaffe, M. B., & Chen, J. (2007) · Cell · doi:10.1016/j.cell.2007.09.041 · Cited by 1,027 · see citing works
Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing
Mimitou, E. P., & Symington, L. S. (2008) · Nature · doi:10.1038/nature07312 · Cited by 1,009 · see citing works
Doil, C., Mailand, N., Bekker‐Jensen, S., Ménard, P., Larsen, D. H., Pepperkok, R., Ellenberg, J., Panier, S., Durocher, D., Bártek, J., et al. (2009) · Cell · doi:10.1016/j.cell.2008.12.041 · Cited by 938 · see citing works
Orchestration of the DNA-Damage Response by the RNF8 Ubiquitin Ligase
Kolas, N. K., Chapman, J. R., Nakada, S., Ylanko, J., Chahwan, R., Sweeney, F. D., Panier, S., Mendez, M., Wildenhain, J., Thomson, T. M., et al. (2007) · Science · doi:10.1126/science.1150034 · Cited by 900 · see citing works
MDC1 is a mediator of the mammalian DNA damage checkpoint
Stewart, G. S., Wang, B., Bignell, C. R., Taylor, A. M. R., & Elledge, S. J. (2003) · Nature · doi:10.1038/nature01446 · Cited by 874 · see citing works
RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation
Tatham, M. H., Geoffroy, M., Shen, L., Plechanovová, A., Hattersley, N., Jaffray, E., Palvimo, J. J., & Hay, R. T. (2008) · Nature Cell Biology · doi:10.1038/ncb1716 · Cited by 837 · see citing works
Self-citationNimonkar, A. V., Genschel, J., Kinoshita, E., Polaczek, P., Campbell, J. L., Wyman, C., Modrich, P. L., & Kowalczykowski, S. C. (2011) · Genes & Development · doi:10.1101/gad.2003811 · Cited by 767 · see citing works
The RIDDLE Syndrome Protein Mediates a Ubiquitin-Dependent Signaling Cascade at Sites of DNA Damage
Stewart, G. S., Panier, S., Townsend, K., Al-Hakim, A., Kolas, N. K., Miller, E. S., Nakada, S., Ylanko, J., Olivarius, S., Mendez, M., et al. (2009) · Cell · doi:10.1016/j.cell.2008.12.042 · Cited by 757 · see citing works
Ubiquitylation and cell signaling
Haglund, K., & Đikić, I. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600808 · Cited by 736 · see citing works
Identification of a SUMO-binding motif that recognizes SUMO-modified proteins
Song, J., Durrin, L. K., Wilkinson, T. A., Krontiris, T. G., & Chen, Y. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403498101 · Cited by 588 · see citing works
CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle
Yun, M. H., & Hiom, K. (2009) · Nature · doi:10.1038/nature07955 · Cited by 556 · see citing works
Principles of ubiquitin and SUMO modifications in DNA repair
Bergink, S., & Jentsch, S. (2009) · Nature · doi:10.1038/nature07963 · Cited by 525 · see citing works
Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks
Galanty, Y., Belotserkovskaya, R., Coates, J., Polo, S. E., Miller, K. M., & Jackson, S. P. (2009) · Nature · doi:10.1038/nature08657 · Cited by 520 · see citing works
High‐resolution profiling of γH2AX around DNA double strand breaks in the mammalian genome
Iacovoni, J. S., Caron, P., Lassadi, I., Nicolas, E., Massip, L., Trouche, D., & Legube, G. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.38 · Cited by 515 · see citing works
Human CtIP Mediates Cell Cycle Control of DNA End Resection and Double Strand Break Repair
Huertas, P., & Jackson, S. P. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808906200 · Cited by 511 · see citing works
MDC1 is required for the intra-S-phase DNA damage checkpoint
Goldberg, M., Stucki, M., Falck, J., D'Amours, D., Rahman, D., Pappin, D., Bartek, J., & Jackson, S. P. (2003) · Nature · doi:10.1038/nature01445 · Cited by 506 · see citing works
System-Wide Changes to SUMO Modifications in Response to Heat Shock
Gołębiowski, F., Matić, I., Tatham, M. H., Cole, C., Yin, Y., Nakamura, A., Cox, J., Barton, G. J., Mann, M., & Hay, R. T. (2009) · Science Signaling · doi:10.1126/scisignal.2000282 · Cited by 485 · see citing works
Self-citationDistinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage.
Lukas, C., Falck, J., Bartkova, J., Bartek, J., & Lukas, J. (2003) · Nature Cell Biology · doi:10.1038/ncb945 · Cited by 474 · see citing works
Wang, B., & Elledge, S. J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710061104 · Cited by 446 · see citing works
The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress
Morris, J. R., Boutell, C., Epple, M., Densham, R. M., Weekes, D. B., Alamshah, A., Butler, L. R., Galanty, Y., Pangon, L., Kiuchi, T., et al. (2009) · Nature · doi:10.1038/nature08593 · Cited by 434 · see citing works
Chen, P., Chen, C., Chen, Y., Xiao, J., Sharp, Z. D., & Lee, W. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.9.5287 · Cited by 394 · see citing works
Mdc1 couples DNA double‐strand break recognition by Nbs1 with its H2AX‐dependent chromatin retention
Lukas, C., Melander, F., Stucki, M., Falck, J., Bekker‐Jensen, S., Goldberg, M., Lerenthal, Y., Jackson, S. P., Bártek, J., & Lukas, J. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600269 · Cited by 387 · see citing works
SUMO‐targeted ubiquitin ligases in genome stability
Prudden, J., Kaeser-Pebernard, S., Raffa, G. D., Slavin, D. A., Perry, J. J. P., Tainer, J. A., McGowan, C. H., & Boddy, M. N. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601838 · Cited by 334 · see citing works
MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways
Lou, Z., Minter‐Dykhouse, K., Wu, X., & Chen, J. (2003) · Nature · doi:10.1038/nature01447 · Cited by 328 · see citing works
Williams, R. S., Dodson, G. E., Limbo, O., Yamada, Y., Williams, J. S., Guenther, G., Classen, S., Glover, J. N. M., Iwasaki, H., Russell, P., et al. (2009) · Cell · doi:10.1016/j.cell.2009.07.033 · Cited by 322 · see citing works
Ubiquitin-dependent Proteolytic Control of SUMO Conjugates
Uzunova, K., Göttsche, K., Miteva, M., Weisshaar, S. R., Glanemann, C., Schnellhardt, M., Niessen, M. T., Scheel, H., Hofmann, K., Johnson, E. S., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706505200 · Cited by 314 · see citing works
Sun, H., Leverson, J. D., & Hunter, T. R. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601839 · Cited by 299 · see citing works
Cellular functions of the BRCA tumour-suppressor proteins
Boulton, S. J. (2006) · Biochemical Society Transactions · doi:10.1042/bst0340633 · Cited by 292 · see citing works
Sugiyama, T., & Kowalczykowski, S. C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203494200 · Cited by 251 · see citing works
An additional role for SUMO in ubiquitin-mediated proteolysis
Geoffroy, M., & Hay, R. T. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2707 · Cited by 250 · see citing works
Self-citationBreak dosage, cell cycle stage and DNA replication influence DNA double strand break response
Zierhut, C., & Diffley, J. F. X. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.111 · Cited by 234 · see citing works
The Yeast Hex3·Slx8 Heterodimer Is a Ubiquitin Ligase Stimulated by Substrate Sumoylation
Xie, Y., Kerscher, O., Kroetz, M. B., McConchie, H. F., Sung, P., & Hochstrasser, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706025200 · Cited by 213 · see citing works
Regulation of DNA Repair through DeSUMOylation and SUMOylation of Replication Protein A Complex
Dou, H., Huang, C., Singh, M. M., Carpenter, P. B., & Yeh, E. T. H. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.07.021 · Cited by 212 · see citing works
Mechanism of ubiquitylation by dimeric RING ligase RNF4
Plechanovová, A., Jaffray, E., McMahon, S. A., Johnson, K. A., Navratilova, I. H., Naismith, J. H., & Hay, R. T. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2108 · Cited by 181 · see citing works
Self-citationA Supramodular FHA/BRCT-Repeat Architecture Mediates Nbs1 Adaptor Function in Response to DNA Damage
Lloyd, J., Chapman, J. R., Clapperton, J. A., Haire, L. F., Hartsuiker, E., Li, J., Carr, A. M., Jackson, S. P., & Smerdon, S. J. (2009) · Cell · doi:10.1016/j.cell.2009.07.043 · Cited by 178 · see citing works
Tatham, M. H., Kim, S., Jaffray, E., et al. (2004) · Nature Structural & Molecular Biology · doi:10.1038/nsmb878 · Cited by 167 · see citing works
Purification and identification of endogenous polySUMO conjugates
Bruderer, R., Tatham, M. H., Plechanovová, A., Matić, I., Garg, A. K., & Hay, R. T. (2011) · EMBO Reports · doi:10.1038/embor.2010.206 · Cited by 167 · see citing works
Self-citationDetection of protein SUMOylation in vivo
Tatham, M. H., Rodríguez, M. S., Xirodimas, D. P., & Hay, R. T. (2009) · Nature Protocols · doi:10.1038/nprot.2009.128 · Cited by 159 · see citing works
Self-citationSUMO Modification Regulates BLM and RAD51 Interaction at Damaged Replication Forks
Ouyang, K. J., Woo, L. L., Zhu, J., Huo, D., Matunis, M. J., & Ellis, N. A. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000252 · Cited by 128 · see citing works
MDC1/NFBD1: a key regulator of the DNA damage response in higher eukaryotes
Stucki, M., & Jackson, S. P. (2004) · DNA repair · doi:10.1016/j.dnarep.2004.03.007 · Cited by 111 · see citing works
Coping with DNA double strand breaks
Hiom, K. J. (2010) · DNA repair · doi:10.1016/j.dnarep.2010.09.018 · Cited by 94 · see citing works
Genome stability roles of SUMO-targeted ubiquitin ligases
Heideker, J., Perry, J. J. P., & Boddy, M. N. (2009) · DNA repair · doi:10.1016/j.dnarep.2009.01.010 · Cited by 36 · see citing works
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Yau, R., & Rape, M. (2016) · Nature Cell Biology · doi:10.1038/ncb3358 · Cited by 1,054 · see citing works
Regulation of DNA Damage Responses by Ubiquitin and SUMO
Jackson, S. P., & Durocher, D. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.017 · Cited by 601 · see citing works
Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis
Plechanovová, A., Jaffray, E. G., Tatham, M. H., Naismith, J. H., & Hay, R. T. (2012) · Nature · doi:10.1038/nature11376 · Cited by 521 · see citing works
Self-citationMaréchal, A., & Zou, L. (2015) · Cell Research · doi:10.1038/cr.2014.147 · Cited by 465 · see citing works
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Yan, S., Sorrell, M., & Berman, Z. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1666-4 · Cited by 247 · see citing works
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Lecona, E., Rodriguez-Acebes, S., Specks, J., Lopez-Contreras, A. J., Ruppen, I., Murga, M., Muñoz, J., Mendez, J., & Fernandez-Capetillo, O. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3185 · Cited by 148 · see citing works
- Authors
- Yin, Y., Seifert, A., Chua, J. S., Maure, J.-F., Golebiowski, F., & Hay, R. T.
- Affiliations
- Wellcome Trust (GB)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-06-01
- Volume
- 26
- Issue
- 11
- Pages
- 1196-1208
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3371408
- OpenAlex
- W2140740835
- Cited by
- 237
- References
- 47
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 11 · 2023: 6 · 2022: 16 · 2021: 14 · 2020: 13 · 2019: 15 · 2018: 9 · 2017: 21 · 2016: 24 · 2015: 26 · 2014: 22 · 2013: 33 · 2012: 10
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Genes & Development (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- Wellcome Trust (098391/Z/12/Z)
- Cancer Research UK (13067)
- Research Councils UK
- Medical Research Council
- European Regional Development Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- RNF4, DNA damage response, SUMOylation, MDC1, ubiquitination, homologous recombination, end resection, CtIP, RAD51, NBS1, 53BP1, RNF8, RNF168, ionizing radiation, DNA double-strand breaks
- MeSH terms
- Animals, DNA Damage, DNA Repair, HeLa Cells, Humans, Nuclear Proteins, Transcription Factors, Trans-Activators, Cell Cycle Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Rats, DNA Breaks, Double-Stranded, Homologous Recombination
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