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Persistent DNA Repair Signaling and DNA Polymerase Theta Promote Broken Chromosome Segregation

Publication ,  Journal Article
Clay, D; Bretscher, H; Jezuit, E; Bush, K; Fox, D
2021

Cycling cells must respond to double-strand breaks (DSBs) to avoid genome instability. Mis-segregation 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 Drosophila 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) to DSBs. This machinery persists as foci on DSBs as cells enter mitosis. Repair foci are resolved in a step-wise manner during mitosis. Repair signaling kinetics at DSBs depends on both monoubiquitination of the Fanconi Anemia (FA) protein Fancd2 and the alternative end-joining protein DNA Polymerase Theta. 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. Clay et. al. show that cells with DNA breaks that persist into mitosis activate sustained DNA repair signaling, regulated by Fanconi Anemia proteins and the alternative end-joining repair protein DNA Polymerase Theta. This signaling enables broken chromosome segregation and prevents micronuclei.

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2021
 

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Clay, D., Bretscher, H., Jezuit, E., Bush, K., & Fox, D. (2021). Persistent DNA Repair Signaling and DNA Polymerase Theta Promote Broken Chromosome Segregation. https://doi.org/10.1101/2021.06.18.449048
Clay, Delisa, Heidi Bretscher, Erin Jezuit, Korie Bush, and Donald Fox. “Persistent DNA Repair Signaling and DNA Polymerase Theta Promote Broken Chromosome Segregation,” 2021. https://doi.org/10.1101/2021.06.18.449048.
Clay, Delisa, et al. Persistent DNA Repair Signaling and DNA Polymerase Theta Promote Broken Chromosome Segregation. 2021. Epmc, doi:10.1101/2021.06.18.449048.

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Publication Date

2021