FANCD2-dependent mitotic DNA synthesis relies on PCNA K164 ubiquitination

Wendy Leung; Ryan M. Baxley; Emma Traband; Ya-Chu Chang; Colette B. Rogers; Liangjun Wang; Wesley Durrett; Kendall S. Bromley; Lidia Fiedorowicz; Tanay Thakar; Anika Tella; Alexandra Sobeck; Eric A. Hendrickson; George-Lucian Moldovan; Naoko Shima; Anja-Katrin Bielinsky

Cell Reports (Dec 2023)

FANCD2-dependent mitotic DNA synthesis relies on PCNA K164 ubiquitination

Wendy Leung,
Ryan M. Baxley,
Emma Traband,
Ya-Chu Chang,
Colette B. Rogers,
Liangjun Wang,
Wesley Durrett,
Kendall S. Bromley,
Lidia Fiedorowicz,
Tanay Thakar,
Anika Tella,
Alexandra Sobeck,
Eric A. Hendrickson,
George-Lucian Moldovan,
Naoko Shima,
Anja-Katrin Bielinsky

Affiliations

Wendy Leung: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
Ryan M. Baxley: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
Emma Traband: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
Ya-Chu Chang: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
Colette B. Rogers: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
Liangjun Wang: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
Wesley Durrett: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
Kendall S. Bromley: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22903, USA
Lidia Fiedorowicz: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22903, USA
Tanay Thakar: Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
Anika Tella: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
Alexandra Sobeck: Institute for Human Genetics, Biocenter, University of Würzburg, Würzburg, Germany
Eric A. Hendrickson: Department of Medicine, University of Virginia, Charlottesville, VA 22903, USA
George-Lucian Moldovan: Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
Naoko Shima: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA; Corresponding author
Anja-Katrin Bielinsky: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22903, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 12
p. 113523

Abstract

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Summary: Ubiquitination of proliferating cell nuclear antigen (PCNA) at lysine 164 (K164) activates DNA damage tolerance pathways. Currently, we lack a comprehensive understanding of how PCNA K164 ubiquitination promotes genome stability. To evaluate this, we generated stable cell lines expressing PCNAK164R from the endogenous PCNA locus. Our data reveal that the inability to ubiquitinate K164 causes perturbations in global DNA replication. Persistent replication stress generates under-replicated regions and is exacerbated by the DNA polymerase inhibitor aphidicolin. We show that these phenotypes are due, in part, to impaired Fanconi anemia group D2 protein (FANCD2)-dependent mitotic DNA synthesis (MiDAS) in PCNAK164R cells. FANCD2 mono-ubiquitination is significantly reduced in PCNAK164R mutants, leading to reduced chromatin association and foci formation, both prerequisites for FANCD2-dependent MiDAS. Furthermore, K164 ubiquitination coordinates direct PCNA/FANCD2 colocalization in mitotic nuclei. Here, we show that PCNA K164 ubiquitination maintains human genome stability by promoting FANCD2-dependent MiDAS to prevent the accumulation of under-replicated DNA.

CP: Molecular biology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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