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RNase H genes cause distinct impacts on RNA:DNA hybrid formation and mutagenesis genome-wide

Jeremy W. Schroeder, Rebecca L. Hurto, Justin R. Randall, Katherine J. Wozniak, Taylor A. Timko, Taylor M. Nye, View ORCID ProfileJue D. Wang, View ORCID ProfilePeter L. Freddolino, View ORCID ProfileLyle A. Simmons
doi: https://doi.org/10.1101/2023.05.08.539860
Jeremy W. Schroeder
1Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109.
2Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
3Department of Bacteriology, University of Wisconsin - Madison, Madison, WI 53706
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Rebecca L. Hurto
1Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109.
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Justin R. Randall
2Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
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Katherine J. Wozniak
2Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
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Taylor A. Timko
2Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
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Taylor M. Nye
2Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
4Department of Molecular Microbiology and Center for Women’s Infectious Disease Research, Washington University School of Medicine, Saint Louis, MO 63110-1093, USA
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Jue D. Wang
3Department of Bacteriology, University of Wisconsin - Madison, Madison, WI 53706
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Peter L. Freddolino
1Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109.
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  • For correspondence: lasimm@umich.edu petefred@umich.edu
Lyle A. Simmons
2Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
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  • For correspondence: lasimm@umich.edu petefred@umich.edu
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ABSTRACT

RNA:DNA hybrids such as R-loops affect genome integrity and DNA replication fork progression. The overall impacts of naturally occurring RNA:DNA hybrids on genome integrity, and the relative contributions of ribonucleases H to mitigating the negative effects of hybrids, remain unknown. Here, we investigate the contributions of RNases HII (RnhB) and HIII (RnhC) to hybrid removal, DNA replication, and mutagenesis genome-wide. Deletion of either rnhB or rnhC triggers RNA:DNA hybrid accumulation, but with distinct patterns of mutagenesis and hybrid accumulation. Across all cells, hybrids accumulate most strongly in non-coding RNAs and 5′-UTRs of coding sequences. For ΔrnhB, hybrids accumulate preferentially in untranslated regions and early in coding sequences. Hybrid accumulation is particularly sensitive to gene expression in ΔrnhC; in cells lacking RnhC, DNA replication is disrupted leading to transversions and structural variation. Our results resolve the outstanding question of how hybrids in native genomic contexts interact with replication to cause mutagenesis and shape genome organization.

Competing Interest Statement

The authors have declared no competing interest.

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  • ↵‡To whom correspondence should be addressed:

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 08, 2023.
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RNase H genes cause distinct impacts on RNA:DNA hybrid formation and mutagenesis genome-wide
Jeremy W. Schroeder, Rebecca L. Hurto, Justin R. Randall, Katherine J. Wozniak, Taylor A. Timko, Taylor M. Nye, Jue D. Wang, Peter L. Freddolino, Lyle A. Simmons
bioRxiv 2023.05.08.539860; doi: https://doi.org/10.1101/2023.05.08.539860
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RNase H genes cause distinct impacts on RNA:DNA hybrid formation and mutagenesis genome-wide
Jeremy W. Schroeder, Rebecca L. Hurto, Justin R. Randall, Katherine J. Wozniak, Taylor A. Timko, Taylor M. Nye, Jue D. Wang, Peter L. Freddolino, Lyle A. Simmons
bioRxiv 2023.05.08.539860; doi: https://doi.org/10.1101/2023.05.08.539860

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