DROSHA is recruited to DNA damage sites by the MRN complex to promote non-homologous end joining
| Autor: | Fabrizio d'Adda di Fagagna, Sofia Francia, Antonio Maffia, Lina Cipolla, Simone Sabbioneda, Matteo Cabrini, Fabio Iannelli, Alessandro Galbiati, Marco Roncador |
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| Přispěvatelé: | University of Zurich, d'Adda di Fagagna, Fabrizio, Francia, Sofia |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
DNA End-Joining Repair
DNA Repair DNA repair DNA damage RAD51 610 Medicine & health Biology 1307 Cell Biology 03 medical and health sciences 0302 clinical medicine DNA Breaks Double-Stranded Homologous Recombination NHEJ Drosha 030304 developmental biology 0303 health sciences Cell Biology Cell biology Non-homologous end joining enzymes and coenzymes (carbohydrates) MRN complex 030220 oncology & carcinogenesis Rad50 10032 Clinic for Oncology and Hematology biological phenomena cell phenomena and immunity Homologous recombination DROSHA Research Article |
| Zdroj: | Journal of Cell Science article-version (VoR) Version of Record |
| Popis: | 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. Summary: DROSHA is part of the primary response to DNA damage and is recruited at double-strand breaks in an MRN-dependent manner. DROSHA fosters NHEJ repair and inhibits HR by controlling 53BP1 recruitment. |
| Databáze: | OpenAIRE |
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