DNA methyltransferases control telomere length and telomere recombination in mammalian cells
DNA methyltransferases control telomere length and telomere recombination in mammalian cells
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DOI：
10.1038/ncb1386
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发表时间：
2006-04-01
影响因子：
21.3
通讯作者：
Blasco, MA
中科院分区：
文献类型：
--
作者：
Gonzalo, S;Jaco, I;Blasco, MA
在这里，我们描述了哺乳动物DNA甲基转移酶（DNMTs）在端粒长度控制中的作用。与野生型对照相比，DNMT1或DNMT3a和DNMT3b基因缺陷的小鼠胚胎干细胞（ES）具有显著延长的端粒。哺乳动物端粒重复序列（TTAGGG）缺乏典型的CpG甲基化位点。然而，我们证明，小鼠的亚端粒区域是严重甲基化，这种修饰在DNMT缺陷细胞减少。我们发现，其他异染色质标记，如组蛋白3赖氨酸9（H3K9）和组蛋白4赖氨酸20（H4K20）三甲基化，仍然在这两个亚端粒和端粒区域在这些细胞。缺乏DNMT也导致端粒重组增加，如涉及端粒序列的姐妹染色单体交换所示，以及存在“端粒替代性延长”（ALT）相关的早幼粒细胞白血病（PML）小体（APB）。这种增加的端粒重组可能会导致端粒长度的变化，虽然我们的研究结果并不排除潜在的参与端粒酶和端粒结合蛋白在DNMT缺陷细胞中观察到的异常端粒延长。总之，这些结果证明了DNA甲基化在维持端粒完整性方面的先前未被重视的作用。
Here, we describe a role for mammalian DNA methyltransferases ( DNMTs) in telomere length control. Mouse embryonic stem ( ES) cells genetically deficient for DNMT1, or both DNMT3a and DNMT3b have dramatically elongated telomeres compared with wild-type controls. Mammalian telomere repeats ( TTAGGG) lack the canonical CpG methylation site. However, we demonstrate that mouse subtelomeric regions are heavily methylated, and that this modification is decreased in DNMT-deficient cells. We show that other heterochromatic marks, such as histone 3 Lys 9 (H3K9) and histone 4 Lys 20 (H4K20) trimethylation, remain at both subtelomeric and telomeric regions in these cells. Lack of DNMTs also resulted in increased telomeric recombination as indicated by sister-chromatid exchanges involving telomeric sequences, and by the presence of 'alternative lengthening of telomeres' (ALT)-associated promyelocytic leukaemia (PML) bodies (APBs). This increased telomeric recombination may lead to telomere-length changes, although our results do not exclude a potential involvement of telomerase and telomere-binding proteins in the aberrant telomere elongation observed in DNMT-deficient cells. Together, these results demonstrate a previously unappreciated role for DNA methylation in maintaining telomere integrity.