p53- and p21-dependent premature APC/C-Cdh1 activation in G2 is part of the long-term response to genotoxic stress.
The long-term cellular response to DNA damage is controlled by the tumor suppressor p53. It results in cell-cycle arrest followed by DNA repair and, depending on the degree of damage inflicted, premature senescence or apoptotic cell death. Here we show that in normal diploid fibroblasts the ubiquitin ligase anaphase-promoting complex or cyclosome (APC/C)-Cdh1 becomes prematurely activated in G2 as part of the sustained long-term but not the rapid short-term response to genotoxic stress and results in the degradation of numerous APC/C substrates. Using HCT116 somatic knockout cells we show that mechanistically premature APC/C activation depends on p53 and its transcriptional target p21 that mediates the signal through downregulation of the APC/C inhibitor Emi1. Cdc14B is dispensable in this setting but might function redundantly. Our data suggest an unexpected role for the APC/C in executing a part of the p53-dependent DNA damage response that leads to premature senescence.
Wiebusch
L
L
Children's Hospital, Laboratory for Molecular Biology, Charité-Universitätsmedizin Berlin, Berlin, Germany. lueder.wiebusch@charite.de
Hagemeier
C
C
D064173:Anaphase-Promoting Complex-Cyclosome; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D004317:Doxorubicin / Q000494:pharmacology; D054637:Dual-Specificity Phosphatases / Q000172:deficiency / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D044783:F-Box Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D010641:Phenotype; D016196:S Phase / Q000187:drug effects / Q000528:radiation effects; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D044783:F-Box Proteins; C498960:FBXO5 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; C474200:CDC14B protein, human; D054637:Dual-Specificity Phosphatases