B-MYB Is Required for Recovery from the DNA Damage–Induced G2 Checkpoint in p53 Mutant Cells

Abstract

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.