Journal
CELL REPORTS
Volume 34, Issue 1, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108565
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Funding
- SIPOD postdoctoral fellowship (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7 [600399]
- CIHR
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [12971]
- Cariplo Foundation [2010.0818, 2014-0812]
- Fondazione Telethon [GGP12059, GGP17111]
- Association for International Cancer Research (AICR-Worldwide Cancer Research Rif) [14-1331]
- Progetti di Ricerca di Interesse Nazionale (PRIN) 2010-2011
- Progetti di Ricerca di Interesse Nazionale (PRIN) 2005
- Italian Ministry of Education Universities and Research EPIGEN Project
- European Research Council advanced grant [322726]
- AriSLA (project DDRNA)
- AriSLA (project ALS'')
- AIRC Special Program 5 per Mille Metastases project [21091]
- AMANDA project Accordo Quadro Regione Lombardia-CNR
- InterSLA project Accordo Quadro Regione Lombardia-CNR
- flagship progetto InterOmics
- Swiss National Science Foundation (SNCF) [31003A_175444]
- European Research Council (ERC) [681630]
- European Research Council (ERC) [322726] Funding Source: European Research Council (ERC)
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The MRN complex promotes transcription by RNAPII at DSBs by melting DNA ends, independent of its nuclease activities. RPA enhances MRN-mediated transcription, and unpaired DNA ends also allow transcription by RNAPII.
The MRE11-RAD50-NBS1 (MRN) complex supports the synthesis of damage-induced long non-coding RNA (dilncRNA) by RNA polymerase II (RNAPII) from DNA double-strand breaks (DSBs) by an unknown mechanism. Here, we show that recombinant human MRN and native RNAPII are sufficient to reconstitute a minimal functional transcriptional apparatus at DSBs. MRN recruits and stabilizes RNAPII at DSBs. Unexpectedly, transcription is promoted independently from MRN nuclease activities. Rather, transcription depends on the ability of MRN to melt DNA ends, as shown by the use of MRN mutants and specific allosteric inhibitors. Single-molecule FRET assays with wild-type and mutant MRN show a tight correlation between the ability to melt DNA ends and to promote transcription. The addition of RPA enhances MRN-mediated transcription, and unpaired DNA ends allow MRN-independent transcription by RNAPII. These results support a model in which MRN generates single-strand DNA ends that favor the initiation of transcription by RNAPII.
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