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<p>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&#xa0;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 m<sup>5</sup>C-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 m<sup>5</sup>C -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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月23日

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  • Adele Alagia,
  • Kamal Ajit,
  • Arianna Di Fazio,
  • Qilin Long,
  • Monika Gullerova

摘要

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.