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Small Cajal body-associated RNA 2 (scaRNA2) regulates DNA repair pathway choice by inhibiting DNA-PK

Author

Listed:
  • Sofie Bergstrand

    (Neo, Karolinska Institutet)

  • Eleanor M. O’Brien

    (Karolinska Institutet)

  • Christos Coucoravas

    (Karolinska Institutet)

  • Dominika Hrossova

    (Karolinska Institutet)

  • Dimitra Peirasmaki

    (Karolinska Institutet)

  • Sandro Schmidli

    (Karolinska Institutet)

  • Soniya Dhanjal

    (Karolinska Institutet)

  • Chiara Pederiva

    (Karolinska Institutet)

  • Lee Siggens

    (Neo, Karolinska Institutet)

  • Oliver Mortusewicz

    (SciLife, Karolinska Institutet)

  • Julienne J. O’Rourke

    (Karolinska Institutet)

  • Marianne Farnebo

    (Neo, Karolinska Institutet
    Karolinska Institutet)

Abstract

Evidence that long non-coding RNAs (lncRNAs) participate in DNA repair is accumulating, however, whether they can control DNA repair pathway choice is unknown. Here we show that the small Cajal body-specific RNA 2 (scaRNA2) can promote HR by inhibiting DNA-dependent protein kinase (DNA-PK) and, thereby, NHEJ. By binding to the catalytic subunit of DNA-PK (DNA-PKcs), scaRNA2 weakens its interaction with the Ku70/80 subunits, as well as with the LINP1 lncRNA, thereby preventing catalytic activation of the enzyme. Inhibition of DNA-PK by scaRNA2 stimulates DNA end resection by the MRN/CtIP complex, activation of ATM at DNA lesions and subsequent repair by HR. ScaRNA2 is regulated in turn by WRAP53β, which binds this RNA, sequestering it away from DNA-PKcs and allowing NHEJ to proceed. These findings reveal that RNA-dependent control of DNA-PK catalytic activity is involved in regulating whether the cell utilizes NHEJ or HR.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28646-5
    DOI: 10.1038/s41467-022-28646-5
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    References listed on IDEAS

    as
    1. 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.
    2. Zhengping Shao & Ryan A. Flynn & Jennifer L. Crowe & Yimeng Zhu & Jialiang Liang & Wenxia Jiang & Fardin Aryan & Patrick Aoude & Carolyn R. Bertozzi & Verna M. Estes & Brian J. Lee & Govind Bhagat & S, 2020. "DNA-PKcs has KU-dependent function in rRNA processing and haematopoiesis," Nature, Nature, vol. 579(7798), pages 291-296, March.
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