Tilman G, Loriot A, Van Beneden A, Arnoult N, Londoño-Vallejo J A, De Smet C, Decottignies A
Faculty of Medicine, Genetic and Epigenetic Alterations of The Genome Group, de Duve Institute, Catholic University of Louvain, Brussels, Belgium.
Oncogene. 2009 Apr 9;28(14):1682-93. doi: 10.1038/onc.2009.23. Epub 2009 Mar 2.
Most human tumor cells acquire immortality by activating the expression of telomerase, a ribonucleoprotein that maintains stable telomere lengths at chromosome ends throughout cell divisions. Other tumors use an alternative mechanism of telomere lengthening (ALT), characterized by high frequencies of telomeric sister chromatid exchanges (T-SCEs). Mechanisms of ALT activation are still poorly understood, but recent studies suggest that DNA hypomethylation of chromosome ends might contribute to the process by facilitating T-SCEs. Here, we show that ALT/T-SCE(high) tumor cells display low DNA-methylation levels at the D4Z4 and DNF92 subtelomeric sequences. Surprisingly, however, the same sequences retained high methylation levels in ALT/T-SCE(high) SV40-immortalized fibroblasts. Moreover, T-SCE rates were efficiently reduced by ectopic expression of active telomerase in ALT tumor cells, even though subtelomeric sequences remained hypomethylated. We also show that hypomethylation of subtelomeric sequences in ALT tumor cells is correlated with genome-wide hypomethylation of Alu repeats and pericentromeric Sat2 DNA sequences. Overall, this study suggests that, although subtelomeric DNA hypomethylation is often coincident with the ALT process in human tumor cells, it is not required for T-SCE.
大多数人类肿瘤细胞通过激活端粒酶的表达而获得永生，端粒酶是一种核糖核蛋白，在整个细胞分裂过程中维持染色体末端端粒长度的稳定。其他肿瘤则采用端粒延长的替代机制（ALT），其特征是端粒姐妹染色单体交换（T-SCE）的频率很高。ALT激活的机制仍知之甚少，但最近的研究表明，染色体末端的DNA低甲基化可能通过促进T-SCE而有助于这一过程。在这里，我们表明ALT/T-SCE（高）肿瘤细胞在D4Z4和DNF92亚端粒序列处显示出低DNA甲基化水平。然而，令人惊讶的是，相同的序列在ALT/T-SCE（高）的SV40永生化成纤维细胞中保留了高甲基化水平。此外，即使亚端粒序列仍然低甲基化，ALT肿瘤细胞中活性端粒酶的异位表达也能有效降低T-SCE率。我们还表明，ALT肿瘤细胞中亚端粒序列的低甲基化与Alu重复序列和着丝粒周围Sat2 DNA序列的全基因组低甲基化相关。总体而言，这项研究表明，尽管亚端粒DNA低甲基化在人类肿瘤细胞中通常与ALT过程同时发生，但它不是T-SCE所必需的。
