Children’s Medical Research Institute, Westmead, NSW 2145, Australia.
Hum Mol Genet. 2011 Dec 1;20(23):4684-92. doi: 10.1093/hmg/ddr402. Epub 2011 Sep 8.
In human cancer cells with telomeres that have been over-lengthened by exogenous telomerase activity, telomere shortening can occur by a process that generates circles of double-stranded telomeric DNA (t-circles). Here, we demonstrate that this telomeretrimming process occurs in cells of the male germline and in normal lymphocytes following mitogen-stimulated upregulation of telomerase activity. Mouse tissues also contain abundant t-circles, suggesting that telomere trimming also contributes to telomere length regulation in mice. In cancer cells and stimulated lymphocytes, the mechanism involves the XRCC3 homologous recombination (HR) protein and generates single-stranded C-rich telomeric DNA. This suggests that, in addition to the well-documented gradual telomere attrition that accompanies cellular replication, there is also a more rapid form of negative telomere length control in normal mammalian cells, which most likely involves HR-mediated removal of telomere loops in the form of t-circles. We therefore propose that this telomere trimming mechanism is an additional factor in the balance between telomere lengthening and telomere shortening in normal human germline and somatic cells that may prevent excessive lengthening by processes such as telomerase activity.
在端粒酶活性过表达导致端粒过度延长的人类癌细胞中，端粒缩短可以通过产生双链端粒 DNA（t 环）的过程发生。在这里，我们证明了这种端粒修剪过程发生在雄性生殖细胞和正常淋巴细胞中，这些细胞在有丝分裂原刺激下端粒酶活性上调。小鼠组织中也含有丰富的 t 环，这表明端粒修剪也有助于小鼠的端粒长度调节。在癌细胞和受刺激的淋巴细胞中，该机制涉及 XRCC3 同源重组（HR）蛋白，并产生富含单链 C 的端粒 DNA。这表明，除了伴随细胞复制的众所周知的逐渐性端粒损耗外，正常哺乳动物细胞中还存在一种更快的负端粒长度控制形式，这很可能涉及 HR 介导的以 t 环形式去除端粒环。因此，我们提出，这种端粒修剪机制是正常人类生殖细胞和体细胞中端粒延长和端粒缩短之间平衡的另一个因素，它可能通过端粒酶活性等过程防止过度延长。
