Abstract
B-Myb, a highly conserved member of the Myb transcription factor family, is expressed ubiquitously in proliferating cells and controls the cell cycle dependent transcription of G2/M-phase genes. Deregulation of B-Myb has been implicated in oncogenesis and loss of genomic stability. We have identified B-Myb as a novel interaction partner of the Mre11-Rad50-Nbs1 (MRN) complex, a key player in the repair of DNA double strand breaks. We show that B-Myb directly interacts with the Nbs1 subunit of the MRN complex and is recruited transiently to DNA-damage sites. In response to DNA-damage B-Myb is phosphorylated by protein kinase GSK3β and released from the MRN complex. A B-Myb mutant that cannot be phosphorylated by GSK3β disturbs the regulation of pro-mitotic B-Myb target genes and leads to inappropriate mitotic entry in response to DNA-damage. Overall, our work suggests a novel function of B-Myb in the cellular DNA-damage signalling.
Highlights
B-Myb is a highly conserved member of the Myb proto-oncogene family that is ubiquitously expressed in proliferating cells and performs essential roles as transcription factor[1]
We have discovered that B-Myb directly interacts with the Mre11-Rad50-Nbs[1] (MRN) complex, a key player in the response to DNA double strand breaks (DSBs)[31,32]
Because loss of B-Myb in mouse ES-cells causes accumulation of DNA DSBs27 we tested if B-Myb associates with the MRN complex, a key player in the repair of DNA DSBs that is recruited to the sites of DSBs (Carney et al.[33]; Tauchi et al.34)
Summary
B-Myb is a highly conserved member of the Myb proto-oncogene family that is ubiquitously expressed in proliferating cells and performs essential roles as transcription factor[1]. Studies of mammalian B-Myb and its Drosophila melanogaster homolog have identified B-Myb as key interaction partner of the evolutionarily conserved Myb-MuvB/DREAM multiprotein complex that regulates the transcription of specific target genes in a cell cycle dependent manner[2,3]. In S-phase, the MuvB core complex associates with B-Myb, which targets it to the promoters of genes required for the G2/M transition and mitosis, thereby activating their transcription[4,5,6,7,8,9,10]. Recent evidence has suggested that the role of B-Myb as a cell cycle regulated transcription factor is only one aspect of its function in proliferating cells. Our work implicates B-Myb for the first time in the cellular response to DNA DSBs
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