HISTONE H4 AND THE MAINTENANCE OF GENOME INTEGRITY
HISTONE H4 AND THE MAINTENANCE OF GENOME INTEGRITY
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DOI：
10.1101/gad.9.14.1716
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发表时间：
1995-07-15
影响因子：
10.5
通讯作者：
SMITH, MM
中科院分区：
文献类型：
--
作者：
MEGEE, PC;MORGAN, BA;SMITH, MM
酿酒酵母通过核分裂的正常进程需要组蛋白H4氨基末端结构域的功能。删除结构域或改变结构域内4个保守赖氨酸残基的突变会导致细胞周期G(2)+M期的显著延迟。单个和多个赖氨酸残基的定点诱变未能将该表型定位到任何特定位点；只有当所有四种赖氨酸都发生突变时，才会观察到这种缺陷。从四个赖氨酸-谷氨酰胺替代等位基因开始，插入一个含有单个额外赖氨酸残基的三肽抑制了G(2)+M细胞周期缺陷。因此，组蛋白H4的氨基末端结构域具有新的遗传功能，依赖于赖氨酸本身的存在，而不是特定的初级肽序列。为了确定这种功能的性质，我们检测了G(2)/M检查点通路缺陷的H4突变体。有丝分裂纺锤体检查点通路的破坏对组蛋白氨基末端结构域突变体的表型没有影响。然而，作为监测DNA完整性途径的一部分，RAD9的破坏导致H4突变体通过核分裂提前进展，并增加细胞死亡。这些结果表明，赖氨酸依赖的组蛋白H4功能是维持基因组完整性所必需的，并且由于该功能丧失而导致的DNA损伤激活了RAD9依赖的G(2)/M检查点途径。
The normal progression of Saccharomyces cerevisiae through nuclear division requires the function of the amino-terminal domain of histone H4. Mutations that delete the domain, or alter 4 conserved lysine residues within the domain, cause a marked delay during the G(2)+M phases of the cell cycle. Site-directed mutagenesis of single and multiple lysine residues failed to map this phenotype to any particular site; the defect was only observed when all four lysines were mutated. Starting with a quadruple lysine-to-glutamine substitution allele, the insertion of a tripeptide containing a single extra lysine residue suppressed the G(2)+M cell cycle defect. Thus, the amino-terminal domain of histone H4 has novel genetic functions that depend on the presence of lysine per se, and not a specific primary peptide sequence. To determine the nature of this function, we examined H4 mutants that were also defective for G(2)/M checkpoint pathways. Disruption of the mitotic spindle checkpoint pathway had no effect on the phenotype of the histone amino-terminal domain mutant. However, disruption of RAD9, which is part of the pathway that monitors DNA integrity, caused precocious progression of the H4 mutant through nuclear division and increased cell death. These results indicate that the lysine-dependent function of histone H4 is required for the maintenance of genome integrity, and that DNA damage resulting from the loss of this function activates the RAD9 dependent G(2)/M checkpoint pathway.