The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Phase separation of 53 BP 1 determines liquid‐like behavior of DNA repair compartments
Open accessAbstract
The DNA damage response (DDR) generates transient repair compartments to concentrate repair proteins and activate signaling factors. The physicochemical properties of these spatially confined compartments and their function remain poorly understood. Here, we establish, based on live cell microscopy and CRISPR/Cas9‐mediated endogenous protein tagging, that 53BP1‐marked repair compartments are dynamic, show droplet‐like behavior, and undergo frequent fusion and fission events. 53BP1 assembly, but not the upstream accumulation of γH2AX and MDC1, is highly sensitive to changes in osmotic pressure, temperature, salt concentration and to disruption of hydrophobic interactions. Phase separation of 53BP1 is substantiated by optoDroplet experiments, which further allowed dissection of the 53BP1 sequence elements that cooperate for light‐induced clustering. Moreover, we found the tumor suppressor protein p53 to be enriched within 53BP1 optoDroplets, and conditions that disrupt 53BP1 phase separation impair 53BP1‐dependent induction of p53 and diminish p53 target gene expression. We thus suggest that 53BP1 phase separation integrates localized DNA damage recognition and repair factor assembly with global p53‐dependent gene activation and cell fate decisions. The DNA damage response effector 53BP1 forms characteristic foci at DNA breaks, which are here found to exhibit liquid droplet‐like self‐compartmentalization important for downstream activation of the p53 tumor suppressor. Self‐compartmentalization of the DNA double‐strand break response effector 53BP1 plays a key role in damage‐induced activation of p53 and its downstream targets.
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Cites
Genome engineering using the CRISPR-Cas9 system
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Coactivator condensation at super-enhancers links phase separation and gene control
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Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination
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Dynamics of DNA Double-Strand Breaks Revealed by Clustering of Damaged Chromosome Domains
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BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair
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Fluctuations in p53 Signaling Allow Escape from Cell-Cycle Arrest
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Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage
Etourneaud, L., Moussa, A., Rass, E., Genet, D., Willaume, S., Chabance-Okumura, C., Wanschoor, P., Picotto, J., Thézé, B., Dépagne, J., et al. (2021) · Science Advances · doi:10.1126/sciadv.abb3799 · Cited by 54
Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance
Li, X., Wang, S., Xie, Y., Jiang, H., Guo, J., Wang, Y., Peng, Z., Hu, M., Wang, M., Wang, J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37013-x · Cited by 27
LC8 enhances 53BP1 foci through heterogeneous bridging of 53BP1 oligomers
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Metadata
- Authors
- Kilic, S., Lezaja, A., Gatti, M., Bianco, E., Michelena, J., Imhof, R., & Altmeyer, M.
- Venue
- The EMBO Journal
- Published
- 2019-07
- Volume
- 38
- Issue
- 16
- Pages
- e101379-e101379
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- OpenAlex
- W2953749471
- Cited by
- 444
- References
- 9
- FWCI
- 15.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
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