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<p>Double-strand breaks (DSBs) are toxic lesions that lead to genome instability. While canonical DSB repair pathways typically operate independently of RNA, growing evidence suggests that RNA:DNA hybrids and nearby transcripts can influence repair outcomes. However, whether transcript RNA can directly serve as a template for DSB repair in human cells remains unclear. In this study, we develop fluorescence and sequencing-based assays to show that RNA-containing oligonucleotides and messenger RNA can serve as templates during DSB repair. We conduct a CRISPR/Cas9-based genetic screen to identify factors that promote RNA-templated DSB repair (RT-DSBR). Of the candidate polymerases, we identify DNA polymerase&#xa0;zeta (Polζ) as a potential reverse transcriptase that facilitates RT-DSBR. Furthermore, analysis of cancer genome sequencing data reveals whole intron deletions - a distinct genomic signature of RT-DSBR that occurs when spliced mRNA guides repair. Altogether, our findings highlight RT-DSBR as an alternative pathway for repairing DSBs in transcribed genes, with potential mutagenic consequences.</p>

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RNA transcripts serve as a template for double-strand break repair in human cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月10日

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  • Manisha Jalan,
  • Alessandra Brambati,
  • Hina Shah,
  • Niamh McDermott,
  • Juber Patel,
  • Yingjie Zhu,
  • Ahmet Doymaz,
  • Julius Wu,
  • Kyrie S. Anderson,
  • Andrea Gazzo,
  • Fresia Pareja,
  • Takafumi N. Yamaguchi,
  • Theodore Vougiouklakis,
  • Sana Ahmed-Seghir,
  • Philippa Steinberg,
  • Anna Neiman-Golden,
  • Benura Azeroglu,
  • Joan Gomez-Aguilar,
  • Edaise M. da Silva,
  • Suleman Hussain,
  • Daniel Higginson,
  • Paul C. Boutros,
  • Nadeem Riaz,
  • Jorge S. Reis-Filho,
  • Simon N. Powell,
  • Agnel Sfeir

摘要

Double-strand breaks (DSBs) are toxic lesions that lead to genome instability. While canonical DSB repair pathways typically operate independently of RNA, growing evidence suggests that RNA:DNA hybrids and nearby transcripts can influence repair outcomes. However, whether transcript RNA can directly serve as a template for DSB repair in human cells remains unclear. In this study, we develop fluorescence and sequencing-based assays to show that RNA-containing oligonucleotides and messenger RNA can serve as templates during DSB repair. We conduct a CRISPR/Cas9-based genetic screen to identify factors that promote RNA-templated DSB repair (RT-DSBR). Of the candidate polymerases, we identify DNA polymerase zeta (Polζ) as a potential reverse transcriptase that facilitates RT-DSBR. Furthermore, analysis of cancer genome sequencing data reveals whole intron deletions - a distinct genomic signature of RT-DSBR that occurs when spliced mRNA guides repair. Altogether, our findings highlight RT-DSBR as an alternative pathway for repairing DSBs in transcribed genes, with potential mutagenic consequences.