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

Nat Commun. 2022 Feb 23;13(1):1015. doi: 10.1038/s41467-022-28646-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA / genetics
  • DNA / metabolism
  • DNA End-Joining Repair
  • DNA Repair
  • DNA-Activated Protein Kinase / genetics
  • DNA-Activated Protein Kinase / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Ku Autoantigen / genetics
  • Ku Autoantigen / metabolism
  • Protein Kinases* / metabolism
  • RNA*


  • DNA-Binding Proteins
  • RNA
  • DNA
  • Protein Kinases
  • DNA-Activated Protein Kinase
  • Ku Autoantigen