Checkpoint adaptation and recovery: back with Polo after the break.
S. cerevisiae cells that are unable to repair a double strand break ultimately escape the DNA damage checkpoint arrest and enter mitosis. This process called 'adaptation' depends on functional Cdc5, a Polo-like kinase, and was long thought to be limited to single-cell organisms. However, the recent finding that Xenopus extracts can adapt to a long-lasting stall in DNA replication indicates that checkpoint adaptation does also occur in multicellular organisms. Interestingly, the Xenopus Polo-like kinase (Plx1) plays an important role in this adaptation. To add to this, data from our laboratory have shown that the human Polo-like kinase (Plk1) is also required for cell cycle reentry following a DNA damage-induced arrest. But here, Plk1 was shown to be required for bona-fide checkpoint recovery, rather than adaptation. That is, Plk1 is required to restart the cell cycle once all of the damage is repaired and checkpoint signaling is turned off. While the target of Plx1 during adaptation is a component of the checkpoint machinery (Claspin), the target of Plk1 during recovery turns out to be a mitotic regulator (Wee1). Here, we discuss some of the remarkable similarities and subtle differences in the molecular mechanisms that control checkpoint adaptation and recovery, and the role of Polo-like kinases therein.
van Vugt
Marcel A T M
MA
Division of Molecular Biology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Medema
René H
RH
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D029867:Xenopus Proteins / Q000378:metabolism*; D014982:Xenopus laevis; D000097869:Polo-Like Kinase 1
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D004317:Doxorubicin; D009687:Nuclear Proteins; D017239:Paclitaxel; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D029702:Schizosaccharomyces pombe Proteins; D029867:Xenopus Proteins; D000097869:Polo-Like Kinase 1; C416368:CLSPN protein, Xenopus; C085875:cdc5 protein, S pombe; C499349:WEE1 protein, human; C101085:Plk1 protein, Xenopus