Stopped for repairs: a new role for nutrient sensing pathways?
In order to prevent division of damaged chromosomes, cells activate a checkpoint to inhibit mitotic progression in order to repair the damaged DNA. Upon detection of DNA damage two downstream checkpoint kinases, Chk1 and Rad53, are activated by the sensor kinase, Mec1, to block the metaphase to anaphase transition and mitotic exit, respectively. Recent data from studies with budding yeast suggested that the DNA damage checkpoint also enlists the cAMP dependent protein kinase (PKA) pathway, which is an integral part of the nutrient sensing mechanism in budding yeast, to inhibit mitosis in response to DNA damage. Genetic and biochemical evidence suggested that the PKA pathway contributes to the inhibition of mitotic progression by mediating the phosphorylation of the APC specificity factor Cdc20. Phosphorylation of Cdc20 assists the activity of the checkpoint pathways in the inhibition of the degradation of mitotic inhibitors securin, Pds1, and the B type cyclin, Clb2, in order to block anaphase and mitotic exit. Cdc20 was phosphorylated following DNA damage in a PKA and Mec1 dependent manner, suggesting PKA activation is dependent on Mec1. Here we discuss possible mechanisms for how PKA activity could be regulated in response to DNA damage and we will also address the implication of these results in evaluating current cancer treatments.
Searle
Jennifer S
JS
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524, USA.
Sanchez
Yolanda
Y
D000818:Animals; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008938:Mitosis / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D029701:Saccharomyces cerevisiae Proteins; C577488:CDC20 protein, human; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases