Cycling cells must respond to DNA double-strand breaks (DSBs) to avoid genome instability. Missegregation of chromosomes with DSBs during mitosis results in micronuclei, aberrant structures linked to disease. How cells respond to DSBs during mitosis is incompletely understood. We previously showed that Drosophilamelanogaster papillar cells lack DSB checkpoints (as observed in many cancer cells). Here, we show that papillar cells still recruit early acting repair machinery (Mre11 and RPA3) and the Fanconi anemia (FA) protein Fancd2 to DSBs. These proteins persist as foci on DSBs as cells enter mitosis. Repair foci are resolved in a stepwise manner during mitosis. DSB repair kinetics depends on both monoubiquitination of Fancd2 and the alternative end-joining protein DNA polymerase θ. Disruption of either or both of these factors causes micronuclei after DNA damage, which disrupts intestinal organogenesis. This study reveals a mechanism for how cells with inactive DSB checkpoints can respond to DNA damage that persists into mitosis.
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6 December 2021
Article|
October 06 2021
Persistent DNA damage signaling and DNA polymerase theta promote broken chromosome segregation
Delisa E. Clay
,
Delisa E. Clay
1
Department of Cell Biology, Duke University School of Medicine, Durham, NC
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Heidi S. Bretscher,
Heidi S. Bretscher
2
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC
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Erin A. Jezuit,
Erin A. Jezuit
2
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC
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Korie B. Bush,
Korie B. Bush
3
University Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC
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Donald T. Fox
1
Department of Cell Biology, Duke University School of Medicine, Durham, NC
2
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC
3
University Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC
Correspondence to Donald T. Fox: don.fox@duke.edu
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Delisa E. Clay
1
Department of Cell Biology, Duke University School of Medicine, Durham, NC
Heidi S. Bretscher
2
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC
Erin A. Jezuit
2
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC
Korie B. Bush
3
University Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC
Correspondence to Donald T. Fox: don.fox@duke.edu
Received:
June 18 2021
Revision Received:
August 24 2021
Accepted:
September 14 2021
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding
Funder(s):
National Institute of General Medical Sciences
- Award Id(s): GM118447
Funder(s):
National Science Foundation
Funder(s):
National Cancer Institute
- Award Id(s): F31CA186545
© 2021 Clay et al.
2021
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2021) 220 (12): e202106116.
Article history
Received:
June 18 2021
Revision Received:
August 24 2021
Accepted:
September 14 2021
Citation
Delisa E. Clay, Heidi S. Bretscher, Erin A. Jezuit, Korie B. Bush, Donald T. Fox; Persistent DNA damage signaling and DNA polymerase theta promote broken chromosome segregation. J Cell Biol 6 December 2021; 220 (12): e202106116. doi: https://doi.org/10.1083/jcb.202106116
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