Dormant origin firing promotes head-on transcription-replication conflicts at transcription termination sites in response to BRCA2 deficiency

Liana Goehring, Sarah Keegan, Sudipta Lahiri, Wenxin Xia, Michael Kong, Judit Jimenez-Sainz, Dipika Gupta, Ronny Drapkin, Ryan B. Jensen, Duncan J. Smith, Eli Rothenberg, David Fenyö and Tony T. Huang ()
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Liana Goehring: New York University School of Medicine
Sarah Keegan: New York University School of Medicine
Sudipta Lahiri: New York University School of Medicine
Wenxin Xia: New York University School of Medicine
Michael Kong: New York University School of Medicine
Judit Jimenez-Sainz: Yale University
Dipika Gupta: New York University School of Medicine
Ronny Drapkin: Perelman School of Medicine
Ryan B. Jensen: Yale University
Duncan J. Smith: New York University
Eli Rothenberg: New York University School of Medicine
David Fenyö: New York University School of Medicine
Tony T. Huang: New York University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract BRCA2 is a tumor suppressor protein responsible for safeguarding the cellular genome from replication stress and genotoxicity, but the specific mechanism(s) by which this is achieved to prevent early oncogenesis remains unclear. Here, we provide evidence that BRCA2 acts as a critical suppressor of head-on transcription-replication conflicts (HO-TRCs). Using Okazaki-fragment sequencing (Ok-seq) and computational analysis, we identified origins (dormant origins) that are activated near the transcription termination sites (TTS) of highly expressed, long genes in response to replication stress. Dormant origins are a source for HO-TRCs, and drug treatments that inhibit dormant origin firing led to a reduction in HO-TRCs, R-loop formation, and DNA damage. Using super-resolution microscopy, we showed that HO-TRC events track with elongating RNA polymerase II, but not with transcription initiation. Importantly, RNase H2 is recruited to sites of HO-TRCs in a BRCA2-dependent manner to help alleviate toxic R-loops associated with HO-TRCs. Collectively, our results provide a mechanistic basis for how BRCA2 shields against genomic instability by preventing HO-TRCs through both direct and indirect means occurring at predetermined genomic sites based on the pre-cancer transcriptome.

Date: 2024
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DOI: 10.1038/s41467-024-48286-1

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