Abstract
Author SummaryDNA is constantly damaged both by factors outside our bodies (such as ultraviolet rays from sunlight) and by factors from within (such as reactive oxygen species produced during metabolism). DNA damage can lead to malfunctioning of genes, and persistent DNA damage can result in developmental disorders or the development of cancer. To ensure proper DNA repair, cells are equipped with an evolutionarily conserved DNA damage checkpoint, which stops proliferation and activates DNA repair mechanisms. Intriguingly, this DNA damage checkpoint responds to DNA damage throughout the cell cycle, except during mitosis. In this work, we have addressed how cells dismantle their DNA damage checkpoint during mitosis to allow cell division to proceed even if there is damaged DNA present. Using the observation that kinases phosphorylate their substrates on evolutionarily conserved, kinase-specific sequence motifs, we have used a combined computational and experimental approach to predict and verify key proteins involved in mitotic checkpoint inactivation. We show that the checkpoint scaffold protein 53BP1 is phosphorylated by the mitotic kinases Cdk1 and Polo-like kinase-1 (Plk1). Furthermore, we find that Plk1 can inactivate the checkpoint kinase Chk2, which is downstream of 53BP1. Plk1 is shown to be a key mediator of mitotic checkpoint inactivation, as cells that cannot activate Plk1 fail to properly dismantle the DNA damage checkpoint during mitosis and instead show DNA damage-induced Chk2 kinase activation. Two related papers, published in PLoS Biology (Vidanes et al., doi:10.1371/journal.pbio.1000286) and PLoS Genetics (Donnianni et al., doi:10.1371/journal.pgen.1000763), similarly investigate the phenomenon of DNA damage checkpoint silencing.
Highlights
Throughout the life of an organism, cellular DNA constantly encounters chemical and radiation-induced damage
The Ataxia Telangiectasia-mutated (ATM)-checkpoint kinase-2 (Chk2) Pathway Is Silenced in Mitosis To identify potential feedback and control mechanisms that extinguish the ATM-Chk2 signaling axis of the G2/M DNA damage checkpoint, we initially investigated whether we could observe silencing of this network under particular cell states or conditions
If the ATM-Chk2 pathway was inactivated upon mitotic entry, clear differences would be expected when interphase cells are compared to mitotic cells following irradiation
Summary
Throughout the life of an organism, cellular DNA constantly encounters chemical and radiation-induced damage. Additional DNA lesions, including mismatched bases, and singleor double-stranded DNA breaks, arise during the process of replication, which is not an error-free process [1] To cope with these types of genotoxic damage, cells activate powerful DNA damage-induced cell cycle checkpoints that coordinate cell cycle arrest with recruitment and activation of the DNA repair machinery [2,3,4,5,6]. To ensure proper DNA repair, cells are equipped with an evolutionarily conserved DNA damage checkpoint, which stops proliferation and activates DNA repair mechanisms. Plk is shown to be a key mediator of mitotic checkpoint inactivation, as cells that cannot activate Plk fail to properly dismantle the DNA damage checkpoint during mitosis and instead show DNA damage-induced Chk kinase activation. Two related papers, published in PLoS Biology (Vidanes et al, doi:10.1371/journal.pbio.1000286) and PLoS Genetics (Donnianni et al, doi:10.1371/journal.pgen.1000763), investigate the phenomenon of DNA damage checkpoint silencing
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