H2B Tyr37 phosphorylation suppresses expression of replication-dependent core histone genes.
H2B Tyr37 phosphorylation suppresses expression of replication-dependent core histone genes.
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DOI：
10.1038/nsmb.2356
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发表时间：
2012-09
影响因子：
16.8
通讯作者：
Mahajan NP
中科院分区：
文献类型：
--
作者：
Mahajan K;Fang B;Koomen JM;Mahajan NP
组蛋白基因转录在DNA合成完成后被主动下调，以避免生产过剩。然而，停止组蛋白mRNA合成的确切机制细节尚不清楚。我们发现，在S晚期，组蛋白H_2B在酪氨酸37处发生磷酸化，位于组蛋白簇1，组蛋白1的上游。我们确定WEE1是在Tyr37处使H2B磷酸化的激酶。在酵母和哺乳动物细胞中，WEE1激酶的表达缺失或抑制会导致H 2B Tyr37的磷酸化，并伴随着组蛋白转录的增加。H2B Tyr37的磷酸化排除了转录共激活因子NPAT和RNA聚合酶II的结合，并招募了组蛋白伴侣Hira位于组蛋白1簇的上游。综上所述，我们的数据显示了WEE1激酶作为一种表观遗传调节器的先前未知和进化上保守的功能，它标志着染色质与H2B Tyr37磷酸化，从而抑制多个组蛋白基因的转录，以减轻组蛋白mRNA周转机制的负担。
Histone gene transcription is actively downregulated after completion of DNA synthesis to avoid overproduction. However, the precise mechanistic details of the cessation of histone mRNA synthesis are not clear. We found that histone H2B phosphorylation at Tyr37 occurs upstream of histone cluster 1, Hist1, during the late S phase. We identified WEE1 as the kinase that phosphorylates H2B at Tyr37. Loss of expression or inhibition of WEE1 kinase abrogated H2B Tyr37 phosphorylation with a concomitant increase in histone transcription in yeast and mammalian cells. H2B Tyr37 phosphorylation excluded binding of the transcriptional coactivator NPAT and RNA polymerase II and recruited the histone chaperone HIRA upstream of the Hist1 cluster. Taken together, our data show a previously unknown and evolutionarily conserved function for WEE1 kinase as an epigenetic modulator that marks chromatin with H2B Tyr37 phosphorylation, thereby inhibiting the transcription of multiple histone genes to lower the burden on the histone mRNA turnover machinery.