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Functional transcription promoters at DNA double-strand breaks mediate RNA-driven phase separation of damage-response factors
Open accessAbstract
Damage-induced long non-coding RNAs (dilncRNA) synthesized at DNA double-strand breaks (DSBs) by RNA polymerase II are necessary for DNA-damage-response (DDR) focus formation. We demonstrate that induction of DSBs results in the assembly of functional promoters that include a complete RNA polymerase II preinitiation complex, MED1 and CDK9. Absence or inactivation of these factors causes a reduction in DDR foci both in vivo and in an in vitro system that reconstitutes DDR events on nucleosomes. We also show that dilncRNAs drive molecular crowding of DDR proteins, such as 53BP1, into foci that exhibit liquid-liquid phase-separation condensate properties. We propose that the assembly of DSB-induced transcriptional promoters drives RNA synthesis, which stimulates phase separation of DDR factors in the shape of foci.
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“One of the most recognizable and common markers of cellular senescence is senescence-associated beta-galactosidase (SA-β-gal)37, which reflects the activity of a lysosomal enzyme that cleaves terminal β-d-galactose residues from β-D-galactosides38.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [38]
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Metadata
- Authors
- Pessina, F., Giavazzi, F., Yin, Y., Gioia, U., Vitelli, V., Galbiati, A., Barozzi, S., Garre, M., Oldani, A., Flaus, A., Cerbino, R., Parazzoli, D., Rothenberg, E., & d’Adda di Fagagna, F.
- Affiliations
- IFOM (IT)
- University of Milan (IT)
- New York University (US)
- Ollscoil na Gaillimhe – University of Galway (IE)
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2019-09-30
- Volume
- 21
- Issue
- 10
- Pages
- 1286-1299
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC6859070
- OpenAlex
- W2975196800
- Cited by
- 360
- References
- 86
- Citations by year
- 2026: 31 · 2025: 48 · 2024: 53 · 2023: 49 · 2022: 63 · 2021: 71 · 2020: 42 · 2019: 2
- FWCI
- 14.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Funders
- Marie Curie international mobility fellowship part of Structured International Post Doc Program
- Fondazione Cariplo (2016-0998)
- Regione Lombardia
- Associazione Italiana per la Ricerca sul Cancro (MFAG 2018-22083)
- AriSLA
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- DNA double-strand breaks, MED1, CDK9, 53BP1, liquid-liquid phase separation, condensate, macromolecular crowding, nucleosome reconstitution, transcriptional promoter
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, DNA, DNA Repair, Gene Expression Regulation, HeLa Cells, Histones, Humans, Osteoblasts, Promoter Regions, Genetic, RNA Polymerase II, Transcription, Genetic, Signal Transduction, Cyclin-Dependent Kinase 9, Cell Line, Tumor, DNA Breaks, Double-Stranded, Mediator Complex Subunit 1, HEK293 Cells, RNA, Long Noncoding, Ataxia Telangiectasia Mutated Proteins
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