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R-loop homeostasis and cancer mutagenesis promoted by the DNA cytosine deaminase APOBEC3B

Jennifer L. McCann, Agnese Cristini, Emily K. Law, Seo Yun Lee, View ORCID ProfileMichael Tellier, Michael A. Carpenter, Chiara Beghè, Jae Jin Kim, Matthew C. Jarvis, Bojana Stefanovska, Nuri A. Temiz, Erik N. Bergstrom, Daniel J. Salamango, Margaret R. Brown, Shona Murphy, View ORCID ProfileLudmil B. Alexandrov, Kyle M. Miller, Natalia Gromak, Reuben S. Harris
doi: https://doi.org/10.1101/2021.08.30.458235
Jennifer L. McCann
1Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota, USA, 55455
2Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA, 55455
3Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, USA, 55455
4Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA, 55455
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Agnese Cristini
5Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, UK, OX1 3RE
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Emily K. Law
1Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota, USA, 55455
2Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA, 55455
3Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, USA, 55455
4Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA, 55455
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Seo Yun Lee
6Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA, 78712
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Michael Tellier
5Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, UK, OX1 3RE
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  • ORCID record for Michael Tellier
Michael A. Carpenter
1Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota, USA, 55455
2Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA, 55455
3Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, USA, 55455
4Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA, 55455
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Chiara Beghè
5Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, UK, OX1 3RE
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Jae Jin Kim
6Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA, 78712
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Matthew C. Jarvis
2Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA, 55455
3Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, USA, 55455
4Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA, 55455
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Bojana Stefanovska
2Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA, 55455
3Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, USA, 55455
4Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA, 55455
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Nuri A. Temiz
2Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA, 55455
7Institute for Health Informatics, University of Minnesota, Minneapolis, MN, USA, 55455
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Erik N. Bergstrom
8Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, California, USA, 92093
9Department of Bioengineering, UC San Diego, La Jolla, California, USA, 92093
10Moores Cancer Center, UC San Diego, La Jolla, CA, 92037, USA
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Daniel J. Salamango
2Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA, 55455
3Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, USA, 55455
4Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA, 55455
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Margaret R. Brown
2Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA, 55455
3Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, USA, 55455
4Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA, 55455
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Shona Murphy
5Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, UK, OX1 3RE
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Ludmil B. Alexandrov
8Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, California, USA, 92093
9Department of Bioengineering, UC San Diego, La Jolla, California, USA, 92093
10Moores Cancer Center, UC San Diego, La Jolla, CA, 92037, USA
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  • ORCID record for Ludmil B. Alexandrov
Kyle M. Miller
6Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA, 78712
11Livestrong Cancer Institutes, Dell Medical School, University of Texas at Austin, Austin, Texas, USA, 78712
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Natalia Gromak
5Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, UK, OX1 3RE
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  • For correspondence: natalia.gromak@path.ox.ac.uk rsh@umn.edu
Reuben S. Harris
1Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota, USA, 55455
2Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA, 55455
3Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, USA, 55455
4Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA, 55455
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  • For correspondence: natalia.gromak@path.ox.ac.uk rsh@umn.edu
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Abstract

The single-stranded DNA cytosine-to-uracil deaminase APOBEC3B is an antiviral protein implicated in cancer. However, its substrates in cells are not fully delineated. Here, APOBEC3B proteomics reveal interactions with a surprising number of R-loop factors. Biochemical experiments show APOBEC3B binding to R-loops in human cells and in vitro. Genetic experiments demonstrate R-loop increases in cells lacking APOBEC3B and decreases in cells overexpressing APOBEC3B. Genome-wide analyses show major changes in the overall landscape of physiological and stimulus-induced R-loops with thousands of differentially altered regions as well as binding of APOBEC3B to many of these sites. APOBEC3 mutagenesis impacts overexpressed genes and splice factor mutant tumors preferentially, and APOBEC3-attributed kataegis are enriched in RTCW consistent with APOBEC3B deamination. Taken together with the fact that APOBEC3B binds single-stranded DNA and RNA and preferentially deaminates DNA, these results support a mechanism in which APOBEC3B mediates R-loop homeostasis and contributes to R-loop mutagenesis in cancer.

Highlights

  • Unbiased proteomics link antiviral APOBEC3B to R-loop regulation

  • Systematic alterations of APOBEC3B levels trigger corresponding changes in R-loops

  • APOBEC3B binds R-loops in living cells and in vitro

  • Bioinformatics analyses support an R-loop deamination and mutation model

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
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-NC-ND 4.0 International license.
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Posted August 31, 2021.
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R-loop homeostasis and cancer mutagenesis promoted by the DNA cytosine deaminase APOBEC3B
Jennifer L. McCann, Agnese Cristini, Emily K. Law, Seo Yun Lee, Michael Tellier, Michael A. Carpenter, Chiara Beghè, Jae Jin Kim, Matthew C. Jarvis, Bojana Stefanovska, Nuri A. Temiz, Erik N. Bergstrom, Daniel J. Salamango, Margaret R. Brown, Shona Murphy, Ludmil B. Alexandrov, Kyle M. Miller, Natalia Gromak, Reuben S. Harris
bioRxiv 2021.08.30.458235; doi: https://doi.org/10.1101/2021.08.30.458235
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R-loop homeostasis and cancer mutagenesis promoted by the DNA cytosine deaminase APOBEC3B
Jennifer L. McCann, Agnese Cristini, Emily K. Law, Seo Yun Lee, Michael Tellier, Michael A. Carpenter, Chiara Beghè, Jae Jin Kim, Matthew C. Jarvis, Bojana Stefanovska, Nuri A. Temiz, Erik N. Bergstrom, Daniel J. Salamango, Margaret R. Brown, Shona Murphy, Ludmil B. Alexandrov, Kyle M. Miller, Natalia Gromak, Reuben S. Harris
bioRxiv 2021.08.30.458235; doi: https://doi.org/10.1101/2021.08.30.458235

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