Basnet Harihar, Su Xue B, Tan Yuliang, Meisenhelder Jill, Merkurjev Daria, Ohgi Kenneth A, Hunter Tony, Pillus Lorraine, Rosenfeld Michael G
1] Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Biomedical Sciences Graduate Program, School of Medicine, University of California San Diego, La Jolla, California 92093, USA.
Division of Biological Sciences, Section of Molecular Biology, UCSD Moores Cancer Center, University of California San Diego, La Jolla, California 92093-0347, USA.
Nature. 2014 Dec 11;516(7530):267-71. doi: 10.1038/nature13736. Epub 2014 Sep 24.
Post-translational histone modifications have a critical role in regulating transcription, the cell cycle, DNA replication and DNA damage repair. The identification of new histone modifications critical for transcriptional regulation at initiation, elongation or termination is of particular interest. Here we report a new layer of regulation in transcriptional elongation that is conserved from yeast to mammals. This regulation is based on the phosphorylation of a highly conserved tyrosine residue, Tyr 57, in histone H2A and is mediated by the unsuspected tyrosine kinase activity of casein kinase 2 (CK2). Mutation of Tyr 57 in H2A in yeast or inhibition of CK2 activity impairs transcriptional elongation in yeast as well as in mammalian cells. Genome-wide binding analysis reveals that CK2α, the catalytic subunit of CK2, binds across RNA-polymerase-II-transcribed coding genes and active enhancers. Mutation of Tyr 57 causes a loss of H2B mono-ubiquitination as well as H3K4me3 and H3K79me3, histone marks associated with active transcription. Mechanistically, both CK2 inhibition and the H2A(Y57F) mutation enhance H2B deubiquitination activity of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex, suggesting a critical role of this phosphorylation in coordinating the activity of the SAGA complex during transcription. Together, these results identify a new component of regulation in transcriptional elongation based on CK2-dependent tyrosine phosphorylation of the globular domain of H2A.
翻译后组蛋白修饰在调节转录、细胞周期、DNA复制及DNA损伤修复中起关键作用。鉴定对转录起始、延伸或终止时转录调节至关重要的新组蛋白修饰尤其令人关注。在此，我们报道了从酵母到哺乳动物中保守的转录延伸调控新层面。这种调控基于组蛋白H2A中高度保守的酪氨酸残基Tyr 57的磷酸化，并由酪蛋白激酶2（CK2）出人意料的酪氨酸激酶活性介导。酵母中H2A的Tyr 57突变或CK2活性的抑制会损害酵母以及哺乳动物细胞中的转录延伸。全基因组结合分析表明，CK2的催化亚基CK2α结合于RNA聚合酶II转录的编码基因和活性增强子。Tyr 57突变导致H2B单泛素化以及与活跃转录相关的组蛋白标记H3K4me3和H3K79me3缺失。从机制上讲，CK2抑制和H2A(Y57F)突变均增强了Spt-Ada-Gcn5乙酰转移酶（SAGA）复合物的H2B去泛素化活性，表明这种磷酸化在转录过程中协调SAGA复合物活性方面起关键作用。总之，这些结果确定了基于CK2依赖的H2A球状结构域酪氨酸磷酸化的转录延伸调控新组分。
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