Polo-like kinase-1 is a target of the DNA damage checkpoint

Jordan Laboratory, Department of Hematology, University Medical Centre Utrecht G 03.647, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.
Nature Cell Biology (Impact Factor: 20.06). 10/2000; 2(9):672-6. DOI: 10.1038/35023629
Source: PubMed

ABSTRACT Polo-like kinases (PLKs) have an important role in several stages of mitosis. They contribute to the activation of cyclin B/Cdc2 and are involved in centrosome maturation and bipolar spindle formation at the onset of mitosis. PLKs also control mitotic exit by regulating the anaphase-promoting complex (APC) and have been implicated in the temporal and spatial coordination of cytokinesis. Experiments in budding yeast have shown that the PLK Cdc5 may be controlled by the DNA damage checkpoint. Here we report the effects of DNA damage on Polo-like kinase-1 (Plk1) in a variety of human cell lines. We show that Plk1 is inhibited by DNA damage in G2 and in mitosis. In line with this, we show that DNA damage blocks mitotic exit. DNA damage does not inhibit the kinase activity of Plk1 mutants in which the conserved threonine residue in the T-loop has been changed to aspartic acid, suggesting that DNA damage interferes with the activation of Plk1. Significantly, expression of these mutants can override the G2 arrest induced by DNA damage. On the basis of these data we propose that Plk1 is an important target of the DNA damage checkpoint, enabling cell-cycle arrests at multiple points in G2 and mitosis.

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Available from: René H Medema, Aug 03, 2015
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    • "Polo-like kinase 1 (PLK1), which is upregulated in many cancers, plays a pivotal role in all phases of mitosis [21]. PLK1 is downregulated at the transcriptional level by p53 as part of the G2/M checkpoint [22] [23] [24] [25] [26]. Thus, p53 null cells are unable to downregulate PLK1 in response to chemotherapy, leading to chemoresistance [25] [26]. "
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    • "After that, the activity of PLK1 is no longer needed. It was previously shown that DNA damage inhibits PLK1 activity (Smits et al., 2000). Other evidence, plus the data presented here, indicate that certain PLK1 activity is needed for DNA damage induced centrosome amplification (Inanç et al., 2010; Liu and Erikson, 2002; Lončarek et al., 2010). "
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    ABSTRACT: DNA damage response (DDR) and the centrosome cycle are two of the most critical processes for maintaining a stable genome in animals. Sporadic evidence suggests a connection between these two processes. Here, we report our findings that six Fanconi Anemia (FA) proteins, including FancI and FancJ, localize to the centrosome. Intriguingly, we found that the localization of FancJ to the mother centrosome is stimulated by a DNA interstrand crosslinker, Mitomycin C (MMC). We further show that, in addition to its role in interstrand crosslinking (ICL) repair, FancJ also regulates the normal centrosome cycle as well as ICL induced centrosome amplification by activating the polo-like kinase 1 (PLK1). We have uncovered a novel function of FancJ in centrosome biogenesis and established centrosome amplification as an integral part of the ICL response.
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    • "Altered expression of Plk1 and MPF is frequently observed in many cancers and has been shown to transform NIH3T3 cells (Takai et al., 2005; van Vugt and Medema, 2005). Additionally studies conducted with constitutively active Plk1 have shown that cells enter mitosis regardless of the presence of a damage signal (Smits et al., 2000). Taken together, these studies argue that the excess levels of Plk1 are likely leading to chromosomal instabilities possibly as a result of premature adaptation of the DNA damage checkpoint response. "
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