期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-28646-5
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资金
- Karolinska Institute
The study reveals that the long non-coding RNA scaRNA2 regulates the choice between error-prone NHEJ and error-free HR DNA repair by inhibiting DNA-PK. This control of DNA repair pathway choice by RNA-dependent regulation of DNA-PK catalytic activity highlights the importance of non-coding RNAs in genomic stability.
Proper repair of DNA double-strand breaks is essential for genomic stability. Here, the authors report that a long non-coding RNA, scaRNA2, inhibits DNA-PK and thereby regulates the choice between error-prone NHEJ and error-free HR DNA repair. 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 WRAP53 beta, 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.
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