Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks.
Open accessAbstract
Nonproteolytic ubiquitylation of chromatin surrounding deoxyribonucleic acid double-strand breaks (DSBs), mediated by the RNF8/RNF168 ubiquitin ligases, plays a key role in recruiting repair factors, including 53BP1 and BRCA1, to reestablish genome integrity. In this paper, we show that human RNF169, an uncharacterized E3 ubiquitin ligase paralogous to RNF168, accumulated in DSB repair foci through recognition of RNF168-catalyzed ubiquitylation products by its motif interacting with ubiquitin domain. Unexpectedly, RNF169 was dispensable for chromatin ubiquitylation and ubiquitin-dependent accumulation of repair factors at DSB sites. Instead, RNF169 functionally competed with 53BP1 and RAP80–BRCA1 for association with RNF168-modified chromatin independent of its catalytic activity, limiting the magnitude of their recruitment to DSB sites. By delaying accumulation of 53BP1 and RAP80 at damaged chromatin, RNF169 stimulated homologous recombination and restrained nonhomologous end joining, affecting cell survival after DSB infliction. Our results show that RNF169 functions in a noncanonical fashion to harness RNF168-mediated protein recruitment to DSB-containing chromatin, thereby contributing to regulation of DSB repair pathway utilization.
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RNF168 promotes 53BP1 and BRCA1 localization to DSBs, while RNF169 competes with 53BP1 and BRCA1 for ubiquitin binding and inhibits this binding.
“While RNF168 promotes 53BP1 and BCRA1 localization to sites of DSBs, RNF169 is a direct inhibitor of this binding. This is because, once RNF168 synthesizes H2A/H2AX ubiquitin chains, RNF169 competes with 53BP1 and BRCA1 for ubiquitin binding (Chen et al., 2012; Panier et al., 2012; Poulsen et al., 2012).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Poulsen et al., 2012
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- Authors
- Poulsen, M., Lukas, C., Lukas, J., Bekker-Jensen, S., & Mailand, N.
- Affiliations
- University of Copenhagen (DK)
- Danish Cancer Society (DK)
- Ubiquitin Signaling Group, Department of Disease Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark 1
- Corresponding author
- Mailand, Niels
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2012-04-09
- Volume
- 197
- Issue
- 2
- Pages
- 189-199
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC3328375
- OpenAlex
- W2152886258
- Cited by
- 146
- References
- 36
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 7 · 2023: 10 · 2022: 8 · 2021: 8 · 2020: 14 · 2019: 11 · 2018: 8 · 2017: 13 · 2016: 8 · 2015: 12 · 2014: 5 · 2013: 20 · 2012: 7
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Lundbeckfonden (R34-2009-3790)
- 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
- RNF168, DNA double-strand break repair, E3 ubiquitin ligase, 53BP1, RAP80, BRCA1, homologous recombination, non-homologous end joining, chromatin recruitment, genome stability
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, Carrier Proteins, Cell Survival, Chromatin, DNA, DNA-Binding Proteins, HeLa Cells, Humans, Nuclear Proteins, Zinc Fingers, BRCA1 Protein, Ubiquitin, RNA Interference, RNA, Small Interfering, Ubiquitin-Protein Ligases, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, DNA Breaks, Double-Stranded, Ubiquitination, Histone Chaperones, HEK293 Cells, Homologous Recombination, DNA End-Joining Repair
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