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

Sofie Bergstrand, Eleanor M. O’Brien, Christos Coucoravas, Dominika Hrossova, Dimitra Peirasmaki, Sandro Schmidli, Soniya Dhanjal, Chiara Pederiva, Lee Siggens, Oliver Mortusewicz, Julienne J. O’Rourke and Marianne Farnebo ()
Additional contact information
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

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28646-5

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