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

Department of Physiological Chemistry I, Biocenter, University of Würzburg, Würzburg, Germany

Requests for reprints: Stefan Gaubatz, University of Würzburg, Am Hubland, 97074 Würzburg, Germany. Phone: 931-318-4138; Fax: 931-318-4150; E-mail: stefan.gaubatz{at}biozentrum.uni-wuerzburg.de.

Key Words: B-MYB • checkpoint recovery • LINC • p53 • DNA damage

In response to DNA damage, several signaling pathways that arrest the cell cycle in G₁ and G₂ are activated. The down-regulation of mitotic genes contributes to the stable maintenance of the G₂ arrest. The human LINC or DREAM complex, together with the B-MYB transcription factor, plays an essential role in the expression of G₂-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 G₂-M gene expression in response to DNA damage in these cells, and, importantly, that B-MYB is required for recovery from the G₂ 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. [Cancer Res 2009;69(9):4073–80]