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Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair

Author

Listed:
  • Wei-Ting Lu

    (MRC Toxicology Unit)

  • Ben R. Hawley

    (MRC Toxicology Unit)

  • George L. Skalka

    (MRC Toxicology Unit)

  • Robert A. Baldock

    (University of Sussex
    University of Pittsburgh Cancer Institute, University of Pittsburgh)

  • Ewan M. Smith

    (MRC Toxicology Unit)

  • Aldo S. Bader

    (MRC Toxicology Unit)

  • Michal Malewicz

    (MRC Toxicology Unit)

  • Felicity Z. Watts

    (University of Sussex)

  • Ania Wilczynska

    (MRC Toxicology Unit)

  • Martin Bushell

    (MRC Toxicology Unit)

Abstract

The error-free and efficient repair of DNA double-stranded breaks (DSBs) is extremely important for cell survival. RNA has been implicated in the resolution of DNA damage but the mechanism remains poorly understood. Here, we show that miRNA biogenesis enzymes, Drosha and Dicer, control the recruitment of repair factors from multiple pathways to sites of damage. Depletion of Drosha significantly reduces DNA repair by both homologous recombination (HR) and non-homologous end joining (NHEJ). Drosha is required within minutes of break induction, suggesting a central and early role for RNA processing in DNA repair. Sequencing of DNA:RNA hybrids reveals RNA invasion around DNA break sites in a Drosha-dependent manner. Removal of the RNA component of these structures results in impaired repair. These results show how RNA can be a direct and critical mediator of DNA damage repair in human cells.

Suggested Citation

  • Wei-Ting Lu & Ben R. Hawley & George L. Skalka & Robert A. Baldock & Ewan M. Smith & Aldo S. Bader & Michal Malewicz & Felicity Z. Watts & Ania Wilczynska & Martin Bushell, 2018. "Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-02893-x
    DOI: 10.1038/s41467-018-02893-x
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    Cited by:

    1. Daniel Gómez-Cabello & George Pappas & Diana Aguilar-Morante & Christoffel Dinant & Jiri Bartek, 2022. "CtIP-dependent nascent RNA expression flanking DNA breaks guides the choice of DNA repair pathway," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Sofie Bergstrand & Eleanor M. O’Brien & Christos Coucoravas & Dominika Hrossova & Dimitra Peirasmaki & Sandro Schmidli & Soniya Dhanjal & Chiara Pederiva & Lee Siggens & Oliver Mortusewicz & Julienne , 2022. "Small Cajal body-associated RNA 2 (scaRNA2) regulates DNA repair pathway choice by inhibiting DNA-PK," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. S. Cohen & A. Guenolé & I. Lazar & A. Marnef & T. Clouaire & D. V. Vernekar & N. Puget & V. Rocher & C. Arnould & M. Aguirrebengoa & M. Genais & N. Firmin & R. A. Shamanna & R. Mourad & V. A. Bohr & V, 2022. "A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Aldo S. Bader & Martin Bushell, 2023. "iMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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