Phosphorylation of the MBF Repressor Yox1p by the DNA Replication Checkpoint Keeps the G1/S Cell-Cycle Transcriptional Program Active
Phosphorylation of the MBF Repressor Yox1p by the DNA Replication Checkpoint Keeps the G1/S Cell-Cycle Transcriptional Program Active
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DOI：
10.1371/journal.pone.0017211
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发表时间：
2011-02-16
期刊：
影响因子：
3.7
通讯作者：
de Bruin, Robertus A. M.
中科院分区：
文献类型：
--
作者：
Caetano, Catia;Klier, Steffi;de Bruin, Robertus A. M.
背景：在裂殖酵母中，裂殖酵母G1/S细胞周期调控的转录依赖于MBF。当细胞退出G1期时，涉及Nrm1p和Yox1p与MBF结合的负反馈环导致转录抑制。然而，S阶段DNA复制检查点反应的激活导致了MBF依赖基因的持续表达。方法/主要发现：本报告表明Yox1p与MBF结合是Nrm1依赖的，Yox1p和Nrm1p相互需要结合和抑制MBF靶标。作为对DNA复制胁迫的响应，Yox1p和Nrm1p都在启动子上与MBF解离，导致MBF靶点的抑制。Yox1p的失活是检查点响应的重要组成部分。CDS1p(人Chk2p)检查点蛋白激酶依赖的Yox1p的磷酸化促进其与MBF转录因子的解离。我们证实在Ser114，Thr115处Yox1p的磷酸化是最大限度地依赖检查点激活G1/S细胞周期转录程序所必需的。结论/意义：本研究表明Ser114，Thr115处Yox1p的检查点依赖的磷酸化导致MBF转录程序的下调。DNA复制检查点对细胞周期转录程序的重塑可能是避免基因组不稳定的重要机制。
Background: In fission yeast Schizosaccharomyces pombe G1/S cell-cycle regulated transcription depends upon MBF. A negative feedback loop involving Nrm1p and Yox1p bound to MBF leads to transcriptional repression as cells exit G1 phase. However, activation of the DNA replication checkpoint response during S phase results in persistent expression of MBF-dependent genes.Methodology/Principal Findings: This report shows that Yox1p binding to MBF is Nrm1-dependent and that Yox1p and Nrm1p require each other to bind and repress MBF targets. In response to DNA replication stress both Yox1p and Nrm1p dissociate from MBF at promoters leading to de-repression of MBF targets. Inactivation of Yox1p is an essential part of the checkpoint response. Cds1p (human Chk2p) checkpoint protein kinase-dependent phosphorylation of Yox1p promotes its dissociation from the MBF transcription factor. We establish that phosphorylation of Yox1p at Ser114, Thr115 is required for maximal checkpoint-dependent activation of the G1/S cell-cycle transcriptional program.Conclusions/Significance: This study shows that checkpoint-dependent phosphorylation of Yox1p at Ser114, Thr115 results in de-repression of the MBF transcriptional program. The remodeling of the cell cycle transcriptional program by the DNA replication checkpoint is likely to comprise an important mechanism for the avoidance of genomic instability.