The Smc5/6 complex counteracts R-loop formation at highly transcribed genes in cooperation with RNase H2

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Abstract

The R-loop is a common transcriptional by-product that consists of an RNA-DNA duplex joined to a displaced strand of genomic DNA. While the effects of R-loops on health and disease are well established, there is still an incomplete understanding of the cellular processes responsible for their removal from eukaryotic genomes. Here, we show that a core regulator of chromosome architecture -the Smc5/6 complex- plays a crucial role in the removal of R-loop structures formed during gene transcription. Consistent with this, budding yeast mutants defective in the Smc5/6 complex and enzymes involved in R-loop resolution show strong synthetic interactions and accumulate high levels of RNA-DNA hybrid structures in their chromosomes. Importantly, we demonstrate that the Smc5/6 complex acts on specific types of RNA-DNA hybrid structures in vivo and promotes R-loop degradation by the RNase H2 enzyme in vitro. Collectively, our results reveal a crucial role for the Smc5/6 complex in the removal of toxic R-loops formed at highly transcribed genes and telomeres.

Data availability

All source Data files have been provided for Figures 2-3, Figure 5-6, and Figure supplements on the Dryad open repository site (DOI: 10.5061/dryad.3xsj3txpg). https://datadryad.org/stash/share/4QICK1jufN1YT0elOow5UKTNIwhKEW-L0WsDZ0W1Dlc

The following data sets were generated

1. D'Amours D
2. et al
(2024) Data from: The Smc5/6 complex counteracts R-loop formation at highly transcribed genes in cooperation with RNase H2
Dryad Digital Repository, doi:10.5061/dryad.3xsj3txpg.

https://dx.doi.org/10.5061/dryad.3xsj3txpg

Article and author information

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Shamayita Roy

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0009-0001-9732-1446
Hemanta Adhikary

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada

Competing interests
The authors declare that no competing interests exist.
Sarah Isler

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada

Competing interests
The authors declare that no competing interests exist.
Damien D'Amours

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada

For correspondence
ddamour2@uottawa.ca

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2183-9951

Funding

Canadian Institutes of Health Research (FDN-167265)

Damien D'Amours

This work was supported by a CIHR grant to Damien D'Amours (FDN-167265). Damien D'Amours is also supported by a Canada Research Chair in Chromatin Dynamics & Genome Architecture (CRC-2017-00064).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.