Journal
JOURNAL OF CELL SCIENCE
Volume 134, Issue 6, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.249706
Keywords
DNA damage; DROSHA; Non-homologous end joining; NHEJ
Categories
Funding
- Associazione Italiana per la Ricerca sul Cancro [12710]
- Ministero dell'Istruzione, dell'Universita e della Ricerca (PRIN 2017)
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [12971]
- Cariplo Foundation [2010.0818, 2014-0812]
- Fondazione Telethon [GGP17111]
- Association for International Cancer Research (AICR-Worldwide Cancer Research) [141331]
- Progetti di Ricerca di Interesse Nazionale (PRIN) 2010-2011
- Italian Ministry of Education Universities and Research EPIGEN Project
- European Research Council [322726]
- 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
- Collegio Ghislieri di Pavia
- Fondazione Cariplo [2014-1215]
- Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (AriSLA
- project DDRNA)
- Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (AriSLA
- project ALS)
- Progetti di Ricerca di Interesse Nazionale (PRIN) 2005
- European Research Council (ERC) [322726] Funding Source: European Research Council (ERC)
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The DDR is a signaling cascade that recognizes DNA double-strand breaks and promotes their resolution via DNA repair pathways. DROSHA is recruited at DSBs by the MRN complex, directing DNA repair towards NHEJ. Inactivation of DROSHA reduces NHEJ and boosts HR frequency.
The DNA damage response (DDR) is the signaling cascade that recognizes DNA double-strand breaks (DSBs) and promotes their resolution via the DNA repair pathways of non-homologous end joining (NHEJ) or homologous recombination (HR). We and others have shown that DDR activation requires DROSHA; however, whether DROSHA exerts its functions by associating with damage sites, what controls its recruitment, and how DROSHA influences DNA repair remains poorly understood. Here, we show that DROSHA associates with DSBs independently of transcription. Neither H2AX, nor ATM or DNA-PK kinase activities are required for recruitment of DROSHA to break sites. Rather, DROSHA interacts with RAD50, and inhibition of the MRN complex by mirin treatment abolishes this interaction. MRN complex inactivation by RAD50 knockdown or mirin treatment prevents DROSHA recruitment to DSBs and, as a consequence, also prevents 53BP1 (also known as TP53BP1) recruitment. During DNA repair, DROSHA inactivation reduces NHEJ and boosts HR frequency. Indeed, DROSHA knockdown also increases the association of downstream HR factors such as RAD51 to DNA ends. Overall, our results demonstrate that DROSHA is recruited at DSBs by the MRN complex and directs DNA repair towards NHEJ.
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