The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index.
RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair
Open accessAbstract
Protein ubiquitylation and sumoylation play key roles in regulating cellular responses to DNA double-strand breaks (DSBs). Here, we show that human RNF4, a small ubiquitin-like modifier (SUMO)-targeted ubiquitin E3 ligase, is recruited to DSBs in a manner requiring its SUMO interaction motifs, the SUMO E3 ligases PIAS1 and PIAS4, and various DSB-responsive proteins. Furthermore, we reveal that RNF4 depletion impairs ubiquitin adduct formation at DSB sites and causes persistent histone H2AX phosphorylation (γH2AX) associated with defective DSB repair, hypersensitivity toward DSB-inducing agents, and delayed recovery from radiation-induced cell cycle arrest. We establish that RNF4 regulates turnover of the DSB-responsive factors MDC1 and replication protein A (RPA) at DNA damage sites and that RNF4-depleted cells fail to effectively replace RPA by the homologous recombination factors BRCA2 and RAD51 on resected DNA. Consistent with previous data showing that RNF4 targets proteins to the proteasome, we show that the proteasome component PSMD4 is recruited to DNA damage sites in a manner requiring its ubiquitin-interacting domains, RNF4 and RNF8. Finally, we establish that PSMD4 binds MDC1 and RPA1 in a DNA damage-induced, RNF4-dependent manner and that PSMD4 depletion cause MDC1 and γH2AX persistence in irradiated cells. RNF4 thus operates as a DSB response factor at the crossroads between the SUMO and ubiquitin systems.
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“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 [67]
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Cites
The DNA-damage response in human biology and disease
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Self-citationThe DNA Damage Response: Making It Safe to Play with Knives
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ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage
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ATR: an essential regulator of genome integrity
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53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks
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Human CtIP promotes DNA end resection
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Self-citationRNF8 Ubiquitylates Histones at DNA Double-Strand Breaks and Promotes Assembly of Repair Proteins
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El‐Deiry, W. S., & Parker, M. I. (2018) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.733663119.793549257
Shivani, A. P., & Rajakumara, E. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.29.673013
Bressac, F., Bargain, T., Kleijwegt, C., Bouchereau, W., Bonnefoy, L., Monier, K., Lomonte, P., & Corpet, A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.24.684316
GNL3 SUMOylation is essential for DNA double-strand break repair by homologous recombination
Yang, Y., Li, Y., Dai, R. S., Chen, C., Zientek, K. D., Reddy, A. P., Xia, Z., Sears, R. C., Sun, X., & Dai, M. (2026) · Nature Communications · doi:10.1038/s41467-026-77013-1
Dss1 facilitates Rad51 recruitment downstream of BRCA2/Brh2 in response to DNA damage
Juhl, L., Busch, L., Bagge, J., Xu, R., Kojić, M., Milisavljević, M., Oestergaard, V. H., Holloman, W. K., & Lisby, M. (2026) · DNA repair · doi:10.1016/j.dnarep.2026.103923
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Rôle des partenaires de CTIP2 dans la latence post-intégrative du VIH-1 : importance de la voie SUMO
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ROS–SUMO Crosstalk in Oxidative Stress: Disease Mechanisms and Reproductive Health
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Sharmin, T., Zhao, M., Manivannan, S., Alharbi, K., Singh, K., Qashqari, F. S., Davis, S., Ward, D. G., & Turnell, A. S. (2026) · Journal of Virology · doi:10.1128/jvi.00582-26
E3 Ubiquitin ligases molecular strategies against proteostasis defects of imperfect ageing
Upadhyay, A., Joshi, V., Amanullah, A., Mishra, R., Verma, R. K., Adlakha, Y. K., Suresh, A. K., Dhiman, R., Bhattacharyya, S., & Mishra, A. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103319
ZIPPing the gaps: A new class of zinc finger proteins orchestrates the DNA damage response
Nonfoux, L., Gagné, J., Kang, B. G., Kang, S.-U., Hendzel, M. J., Dawson, T. M., Dawson, V. L., Masson, J., & Poirier, G. G. (2026) · DNA repair · doi:10.1016/j.dnarep.2026.103960
SUMOylation in skin homeostasis and disease: Regulation of cutaneous signaling networks
Li, P., Li, L., Huang, H., & Zhu, M. (2026) · Cellular Signalling · doi:10.1016/j.cellsig.2026.112900
Li, J., Huang, H., Wang, M., & Hang, Q. (2026) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2026.189724
Metadata
- Authors
- Galanty, Y., Belotserkovskaya, R., Coates, J., & Jackson, S. P.
- Affiliations
- University of Cambridge (GB)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-06-01
- Volume
- 26
- Issue
- 11
- Pages
- 1179-1195
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3371407
- OpenAlex
- W2113354406
- Cited by
- 314
- References
- 68
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 15 · 2023: 14 · 2022: 20 · 2021: 19 · 2020: 19 · 2019: 16 · 2018: 14 · 2017: 30 · 2016: 37 · 2015: 27 · 2014: 26 · 2013: 37 · 2012: 15
- Type
- posted content
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (092096)
- Cancer Research UK (C6/A11226, 11224, A11224)
- 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
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- RNF4, DNA double-strand break repair, SUMO interaction motif, PIAS1, PIAS4, H2AX phosphorylation, MDC1, replication protein A, BRCA2, RAD51, homologous recombination, proteasome, PSMD4, RNF8, radiation-induced cell cycle arrest, DNA damage response
- MeSH terms
- DNA Repair, DNA, Single-Stranded, Histones, Humans, Nuclear Proteins, Transcription Factors, Trans-Activators, Cell Cycle Proteins, Ubiquitin-Protein Ligases, Cell Line, Tumor, Proteasome Endopeptidase Complex, Adaptor Proteins, Signal Transducing, Rad51 Recombinase, Replication Protein A, DNA Breaks, Double-Stranded
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