Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks
Open accessAbstract
The DNA damage response (DDR) preserves genomic integrity. Small non-coding RNAs termed DDRNAs are generated at DNA double-strand breaks (DSBs) and are critical for DDR activation. Here we show that active DDRNAs specifically localize to their damaged homologous genomic sites in a transcription-dependent manner. Following DNA damage, RNA polymerase II (RNAPII) binds to the MRE11-RAD50-NBS1 complex, is recruited to DSBs and synthesizes damage-induced long non-coding RNAs (dilncRNAs) from and towards DNA ends. DilncRNAs act both as DDRNA precursors and by recruiting DDRNAs through RNA-RNA pairing. Together, dilncRNAs and DDRNAs fuel DDR focus formation and associate with 53BP1. Accordingly, inhibition of RNAPII prevents DDRNA recruitment, DDR activation and DNA repair. Antisense oligonucleotides matching dilncRNAs and DDRNAs impair site-specific DDR focus formation and DNA repair. We propose that DDR signalling sites, in addition to sharing a common pool of proteins, individually host a unique set of site-specific RNAs necessary for DDR activation.
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Sequence-specific inhibition of DDR activation using antisense oligonucleotides, and their application in cultured cells and mouse models to inhibit telomeric DDR, support this approach.
“Recently, sequence-specific inhibition of DDR activation by antisense oligonucleotides (ASOs)250 and their use in cultured cells and in mouse models to specifically inhibit telomeric DDR38 provided support for this approach.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [250]
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- Authors
- Michelini, F., Pitchiaya, S., Vitelli, V., Sharma, S., Gioia, U., Pessina, F., Cabrini, M., Wang, Y., Capozzo, I., Iannelli, F., Matti, V., Francia, S., Shivashankar, G. V., Walter, N. G., & d’Adda di Fagagna, F.
- Affiliations
- IFOM (IT)
- University of Michigan (US)
- Istituto di Genetica Molecolare (IT)
- National University of Singapore (SG)
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2017-11-27
- Volume
- 19
- Issue
- 12
- Pages
- 1400-1411
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC5714282
- OpenAlex
- W2771049305
- Cited by
- 392
- References
- 57
- Citations by year
- 2026: 26 · 2025: 32 · 2024: 40 · 2023: 55 · 2022: 63 · 2021: 62 · 2020: 50 · 2019: 42 · 2018: 19 · 2017: 1 · 2016: 2
- FWCI
- 12.50
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM098023, R01GM062357)
- National Institute of Allergy and Infectious Diseases (R21AI109791)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- DNA damage response, long non-coding RNA, DNA double-strand breaks, RNA polymerase II, Mre11-Rad50-Nbs1 complex, 53BP1, DNA repair, antisense oligonucleotides
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, MRE11 Homologue Protein, Animals, Cell Line, Cell-Free System, DNA Damage, DNA Repair, DNA-Binding Proteins, Models, Biological, Nuclear Proteins, RNA Polymerase II, Transcription, Genetic, Oligonucleotides, Antisense, Acid Anhydride Hydrolases, ATP-Binding Cassette Transporters, Cell Cycle Proteins, Mice, DNA Breaks, Double-Stranded, RNA, Long Noncoding
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