NSUN2 facilitates DICER cleavage of DNA damage-associated R-loops to promote repair

Adele Alagia, Kamal Ajit, Arianna Fazio, Qilin Long and Monika Gullerova ()
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Adele Alagia: Sir William Dunn School of Pathology
Kamal Ajit: Sir William Dunn School of Pathology
Arianna Fazio: Sir William Dunn School of Pathology
Qilin Long: Sir William Dunn School of Pathology
Monika Gullerova: Sir William Dunn School of Pathology

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract DNA integrity is constantly challenged by both endogenous and exogenous damaging agents, resulting in various forms of damage. Failure to repair DNA accurately leads to genomic instability, a hallmark of cancer. Distinct pathways exist to repair different types of DNA damage. Double-strand breaks (DSBs) represent a particularly severe form of damage, due to the physical separation of DNA strands. The repair of DSBs requires the activity of RNA Polymerase II (RNAPII) and the generation of Damage-responsive transcripts (DARTs). Here we show that the RNA m5C-methyltransferase NSUN2 localises to DSBs in a transcription-dependent manner, where it binds to and methylates DARTs. The depletion of NSUN2 results in an accumulation of nascent primary DARTs around DSBs. Furthermore, we detect an RNA-dependent interaction between NSUN2 and DICER, which is stimulated by DNA damage. NSUN2 activity promotes DICER cleavage of DARTs-associated R-loops, which is required for efficient DNA repair. We report a role of the RNA m5C -methyltransferase NSUN2 within the RNA-dependent DNA damage response, highlighting its function as a DICER chaperone for the clearance of non-canonical substrates such as DARTs, thereby contributing to genomic integrity.

Date: 2025
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DOI: 10.1038/s41467-025-63220-9

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