Damage-induced LncRNAs Control the DNA Damage Response Through Interaction with DDRNAs at Individual Double-strand Breaks
Overview
Authors
Affiliations
The DNA damage response (DDR) preserves genomic integrity. Small non-coding RNAs termed DDRNAs are generated at DNA double-strand breaks (DSBs) and are critical for DDR activation. Here we show that active DDRNAs specifically localize to their damaged homologous genomic sites in a transcription-dependent manner. Following DNA damage, RNA polymerase II (RNAPII) binds to the MRE11-RAD50-NBS1 complex, is recruited to DSBs and synthesizes damage-induced long non-coding RNAs (dilncRNAs) from and towards DNA ends. DilncRNAs act both as DDRNA precursors and by recruiting DDRNAs through RNA-RNA pairing. Together, dilncRNAs and DDRNAs fuel DDR focus formation and associate with 53BP1. Accordingly, inhibition of RNAPII prevents DDRNA recruitment, DDR activation and DNA repair. Antisense oligonucleotides matching dilncRNAs and DDRNAs impair site-specific DDR focus formation and DNA repair. We propose that DDR signalling sites, in addition to sharing a common pool of proteins, individually host a unique set of site-specific RNAs necessary for DDR activation.
Iskandar M, Xiao Barbero M, Jaber M, Chen R, Gomez-Guevara R, Cruz E Cancers (Basel). 2025; 17(2).
PMID: 39858038 PMC: 11764024. DOI: 10.3390/cancers17020257.
Kyriukha Y, Watkins M, Redington J, Chintalapati N, Ganti A, Dastvan R iScience. 2024; 27(12):111259.
PMID: 39584160 PMC: 11582789. DOI: 10.1016/j.isci.2024.111259.
53BP1-the 'Pandora's box' of genome integrity.
Kilgas S, Swift M, Chowdhury D DNA Repair (Amst). 2024; 144:103779.
PMID: 39476547 PMC: 11611608. DOI: 10.1016/j.dnarep.2024.103779.
Tetrameric INTS6-SOSS1 complex facilitates DNA:RNA hybrid autoregulation at double-strand breaks.
Long Q, Ajit K, Sedova K, Haluza V, Stefl R, Dokaneheifard S Nucleic Acids Res. 2024; 52(21):13036-13056.
PMID: 39445827 PMC: 11602137. DOI: 10.1093/nar/gkae937.
From silence to symphony: transcriptional repression and recovery in response to DNA damage.
Ajit K, Gullerova M Transcription. 2024; 15(3-5):161-175.
PMID: 39353089 PMC: 11810087. DOI: 10.1080/21541264.2024.2406717.