RAD51 protects human cells from transcription-replication conflicts
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Oncogene activation during tumorigenesis promotes DNA replication stress (RS), which subsequently drives the formation of cancer-associated chromosomal rearrangements. Many episodes of physiological RS likely arise due to conflicts between the DNA replication and transcription machineries operating simultaneously at the same loci. One role of the RAD51 recombinase in human cells is to protect replication forks undergoing RS. Here, we have identified a key role for RAD51 in preventing transcription-replication conflicts (TRCs) from triggering replication fork breakage. The genomic regions most affected by RAD51 deficiency are characterized by being replicated and transcribed in early S-phase and show significant overlap with loci prone to cancer-associated amplification. Consistent with a role for RAD51 in protecting against transcription-replication conflicts, many of the adverse effects of RAD51 depletion are ameliorated by inhibiting early S-phase transcription. We propose a model whereby RAD51 suppresses fork breakage and subsequent inadvertent amplification of genomic loci prone to experiencing TRCs.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Molecular Cell |
| Vol/bind | 82 |
| Udgave nummer | 18 |
| Sider (fra-til) | 3366-3381.e9 |
| ISSN | 1097-2765 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
We thank Jorge Zepeda (Lexogen services) and Lea H. Gregersen (University of Copenhagen) for advice on nascent transcriptome analysis, Malgorzata Clausen and Marisa M. Goncalves Dinis for technical help with FISH analysis, and André Nussenzweig (NCI, NIH, Bethesda) for sharing the co-ordinates of mouse ERFS. Work in the authors’ laboratories is supported by the Danish National Research Foundation (DNRF115, to I.D.H.), the Nordea Foundation (to I.D.H.), the Swiss National Science Foundation (project 182487, to T.D.H.), and the European Commission (ERC Project REPLISTRESS, to T.D.H.). I.D.H. and R.B. conceived the project and designed the experiments. R.B. performed experiments with help from S.A.G. (for QIBC analysis), M.I.S. (for SLAM-seq), and Y.L. (for FISH). G.G.R. and T.D.H. contributed the MiDAS-seq experiments. M.L. performed all bioinformatic analysis. I.D.H. R.B. and M.L. analyzed data and wrote the manuscript, and all the authors edited it. The authors confirm that there are no relevant financial or nonfinancial competing interests to report.
Funding Information:
We thank Jorge Zepeda (Lexogen services) and Lea H. Gregersen (University of Copenhagen) for advice on nascent transcriptome analysis, Malgorzata Clausen and Marisa M. Goncalves Dinis for technical help with FISH analysis, and André Nussenzweig (NCI, NIH, Bethesda) for sharing the co-ordinates of mouse ERFS. Work in the authors’ laboratories is supported by the Danish National Research Foundation ( DNRF115 , to I.D.H.), the Nordea Foundation (to I.D.H.), the Swiss National Science Foundation (project 182487 , to T.D.H.), and the European Commission (ERC Project REPLISTRESS, to T.D.H.).
Publisher Copyright:
© 2022 Elsevier Inc.
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