The histone methyltransferase SET8 is required for S-phase progression.
The histone methyltransferase SET8 is required for S-phase progression.
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DOI：
10.1083/jcb.200706150
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发表时间：
2007-12-31
期刊：
影响因子：
--
通讯作者：
Sørensen CS
中科院分区：
文献类型：
--
作者：
Jørgensen S;Elvers I;Trelle MB;Menzel T;Eskildsen M;Jensen ON;Helleday T;Helin K;Sørensen CS
染色质的结构和功能受到组蛋白翻译后修饰的影响。SET 8（也称为PR-Set 7和SETD 8）是使组蛋白H4-K20单甲基化的组蛋白甲基转移酶。然而，尚未确定SET 8在哺乳动物细胞增殖中的功能。我们表明，小干扰RNA抑制SET 8表达导致细胞增殖减少和S期细胞的积累。这伴随着DNA双链断裂（DSB）诱导和DNA修复蛋白复制蛋白A、Rad 51和53 BP 1向受损区域的募集。SET 8缺失导致DNA损伤，特别是在复制过程中，诱导Chk 1介导的S期检查点。此外，我们发现SET 8通过保守的基序与增殖细胞核抗原相互作用，并且SET 8是DNA复制叉进展所必需的。最后，编码一种重要的同源重组修复蛋白Rad 51，消除了SET 8缺失后的DNA损伤。总体而言，我们表明，SET 8是必不可少的哺乳动物细胞的基因组稳定性和降低表达SET 8的结果在DNA损伤和Chk 1依赖的S期阻滞。
Chromatin structure and function is influenced by histone posttranslational modifications. SET8 (also known as PR-Set7 and SETD8) is a histone methyltransferase that monomethylates histonfe H4-K20. However, a function for SET8 in mammalian cell proliferation has not been determined. We show that small interfering RNA inhibition of SET8 expression leads to decreased cell proliferation and accumulation of cells in S phase. This is accompanied by DNA double-strand break (DSB) induction and recruitment of the DNA repair proteins replication protein A, Rad51, and 53BP1 to damaged regions. SET8 depletion causes DNA damage specifically during replication, which induces a Chk1-mediated S-phase checkpoint. Furthermore, we find that SET8 interacts with proliferating cell nuclear antigen through a conserved motif, and SET8 is required for DNA replication fork progression. Finally, codepletion of Rad51, an important homologous recombination repair protein, abrogates the DNA damage after SET8 depletion. Overall, we show that SET8 is essential for genomic stability in mammalian cells and that decreased expression of SET8 results in DNA damage and Chk1-dependent S-phase arrest.
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