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

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. Silva, Suleman Hussain, Daniel Higginson, Paul C. Boutros, Nadeem Riaz, Jorge S. Reis-Filho, Simon N. Powell () and Agnel Sfeir ()
Additional contact information
Manisha Jalan: Memorial Sloan Kettering Cancer Center
Alessandra Brambati: Memorial Sloan Kettering Cancer Center
Hina Shah: Memorial Sloan Kettering Cancer Center
Niamh McDermott: Memorial Sloan Kettering Cancer Center
Juber Patel: Memorial Sloan Kettering Cancer Center
Yingjie Zhu: Memorial Sloan Kettering Cancer Center
Ahmet Doymaz: Memorial Sloan Kettering Cancer Center
Julius Wu: Memorial Sloan Kettering Cancer Center
Kyrie S. Anderson: Memorial Sloan Kettering Cancer Center
Andrea Gazzo: Memorial Sloan Kettering Cancer Center
Fresia Pareja: Memorial Sloan Kettering Cancer Center
Takafumi N. Yamaguchi: University of California
Theodore Vougiouklakis: Memorial Sloan Kettering Cancer Center
Sana Ahmed-Seghir: Memorial Sloan Kettering Cancer Center
Philippa Steinberg: University of California
Anna Neiman-Golden: University of California
Benura Azeroglu: National Institutes of Health (NIH)
Joan Gomez-Aguilar: Memorial Sloan Kettering Cancer Center
Edaise M. Silva: Memorial Sloan Kettering Cancer Center
Suleman Hussain: Memorial Sloan Kettering Cancer Center
Daniel Higginson: Memorial Sloan Kettering Cancer Center
Paul C. Boutros: University of California
Nadeem Riaz: Memorial Sloan Kettering Cancer Center
Jorge S. Reis-Filho: Memorial Sloan Kettering Cancer Center
Simon N. Powell: Memorial Sloan Kettering Cancer Center
Agnel Sfeir: Memorial Sloan Kettering Cancer Center

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

Abstract: 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.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59510-x

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DOI: 10.1038/s41467-025-59510-x

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