Rahman Ruman, Forsyth Nicholas R, Cui Wei
Department of Gene Function & Development, Roslin Institute, Roslin, Midlothian EH25 9PS, UK.
Exp Gerontol. 2008 Apr;43(4):258-65. doi: 10.1016/j.exger.2008.01.005. Epub 2008 Jan 26.
Telomeres are specialized DNA/protein complexes that cap eukaryotic chromosome ends as T-loop structures and maintain genomic integrity. Vertebrate telomeric DNA consists of tandem double-strand repeats which terminate in a 3' single-strand G-rich overhang. The telomeric 3'-overhang is important for the formation of the T-loop. In mammalian mortal somatic cells, telomeres shorten with each successive division and contribute to the onset of replicative senescence. The exact molecular mechanism underlying replicative senescence remains unclear: whether telomere shortening is the only trigger or loss of telomeric 3'-overhang plays a causal role. To further address this issue, we investigated telomeric 3'-overhang and telomere changes during cell proliferation toward replicative senescence. We demonstrate here that telomeric 3'-overhang, similar to telomeres, exhibits progressive attrition with each cell division in primary sheep fibroblasts and that telomeric 3'-overhang size does not determine the rate of telomere shortening. Furthermore, the sizes of telomeric 3'-overhangs are associated with telomere lengths. Our results suggest that alteration of the 3'-overhang and the telomere during cellular proliferation are associated. Together they may contribute to maintain chromosomal stability and to regulate replicative senescence.
端粒是一种特殊的DNA/蛋白质复合物，它以T环结构覆盖真核染色体末端并维持基因组完整性。脊椎动物的端粒DNA由串联双链重复序列组成，其末端为富含鸟嘌呤的3'单链突出端。端粒的3'突出端对于T环的形成很重要。在哺乳动物的终末体细胞中，端粒随着每次连续分裂而缩短，并导致复制性衰老的发生。复制性衰老的确切分子机制仍不清楚：端粒缩短是否是唯一的触发因素，或者端粒3'突出端的丧失是否起因果作用。为了进一步解决这个问题，我们研究了细胞增殖至复制性衰老过程中端粒3'突出端和端粒的变化。我们在此证明，与端粒类似，端粒3'突出端在原代绵羊成纤维细胞的每次细胞分裂中都呈现渐进性损耗，并且端粒3'突出端的大小并不决定端粒缩短的速率。此外，端粒3'突出端的大小与端粒长度相关。我们的结果表明，细胞增殖过程中端粒3'突出端和端粒的改变是相关的。它们共同作用可能有助于维持染色体稳定性并调节复制性衰老。
