B-MYB is required for recovery from the DNA damage-induced G2 checkpoint in p53 mutant cells.
In response to DNA damage, several signaling pathways that arrest the cell cycle in G(1) and G(2) are activated. The down-regulation of mitotic genes contributes to the stable maintenance of the G(2) arrest. The human LINC or DREAM complex, together with the B-MYB transcription factor, plays an essential role in the expression of G(2)-M genes. Here, we show that DNA damage results in the p53-dependent binding of p130 and E2F4 to LINC and the dissociation of B-MYB from LINC. We find that B-MYB fails to dissociate from LINC in p53 mutant cells, that this contributes to increased G(2)-M gene expression in response to DNA damage in these cells, and, importantly, that B-MYB is required for recovery from the G(2) DNA damage checkpoint in p53-negative cells. Reanalysis of microarray expression data sets revealed that high levels of B-MYB correlate with a p53 mutant status and an advanced tumor stage in primary human breast cancer. Taken together, these data suggest that B-MYB/LINC plays an important role in the DNA damage response downstream of p53.
Mannefeld
Mirijam
M
Department of Physiological Chemistry I, Biocenter, University of Würzburg, Würzburg, Germany.
Klassen
Elena
E
Gaubatz
Stefan
S
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D016195:G2 Phase / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493841:BCAR1 protein, human; D018797:Cell Cycle Proteins; D050719:Crk-Associated Substrate Protein; C496749:KCNIP3 protein, human; D051605:Kv Channel-Interacting Proteins; C501563:LIN9 protein, human; C064352:MYBL2 protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; C495901:TP53 protein, human; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin