The DNA damage and the DNA synthesis checkpoints converge at the MBF transcription factor

Abstract

DNA damage is an ongoing threat to both the ability of the cell to faithfully transmit genetic information to its offspring as well as to its own survival. In order to maintain genomic integrity, eukaryotes have developed a highly conserved mechanism to detect, signal and repair damage in DNA, known as the DNA damage response (DDR). In fission yeast the two DDR pathways converge at the regulation of single transcriptional factor complex (MBF) resulting in opposite directions. We have shown that when the DNA-synthesis checkpoint is activated, Max1 is phosphorylated by Cds1 resulting in the abrogation of its binding to MBF. As a consequence, MBF-dependent transcription is maintained active until cells are able to overcome the replication challenge. In contrast, upon DNA damage, Chk1 the effector kinase of DNA damage checkpoint is activated and blocks the cell cycle progression, inducing DNA repair and repressing the MBF dependent transcription. We have revealed that Cdc10 is the target of the DNA-damage checkpoint and when cells are treated with MMS or are exposed to IR, Chk1 phosphorylates Cdc10 inducing the exit of MBF from chromatin. The consequence is that under these conditions, MBF-dependent transcription is repressed. Thus, Max1 and Cdc10 couple normal cell cycle regulation and the DNA-synthesis and DNA-damage checkpoints into MBF.