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

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

Abstract 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...

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Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2025-05-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-59510-x
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Summary:Abstract 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.
ISSN:2041-1723

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