Expression of telomerase RNA template, but not telomerase reverse transcriptase, is limiting for telomere length maintenance in vivo
Expression of telomerase RNA template, but not telomerase reverse transcriptase, is limiting for telomere length maintenance in vivo
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DOI：
10.1128/mcb.24.16.7024-7031.2004
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发表时间：
2004-08-01
影响因子：
5.3
通讯作者：
Hodes, RJ
中科院分区：
文献类型：
--
作者：
Chiang, YJ;Hemann, MT;Hodes, RJ
端粒酶由端粒酶RNA模板和端粒酶逆转录酶两个基本成分组成。新近发现，一种人类先天性角化不良的表现为端粒异常缩短的遗传性疾病，是一种由TR基因缺失引起的遗传病。与这一发现一致的是，我们最近报道了小鼠TR失活的杂合子小鼠表现出类似的单倍体不足，并在体内缺乏延长端粒的能力。为了进一步评估端粒酶活性的遗传调控，我们比较了TRR缺陷小鼠和TERT缺陷小鼠在物种间杂交中维持或延长端粒的能力。纯合子TERT基因敲除小鼠没有端粒酶活性，也无法维持端粒长度。相反，与野生型对照相比，TERT+/-杂合子在端粒伸长方面没有检测到缺陷，而tr+/-杂合子在端粒伸长方面存在缺陷。杂合子小鼠的TERT mRNA水平是野生型小鼠表达水平的三分之一到一半，类似于观察到的tr杂合子小鼠端粒酶RNA的减少。这些发现表明，在所分析的体内条件下，TR和TERT对端粒的维持和延长都是必不可少的，但在所分析的体内条件下，基因拷贝数和TR的转录调控，而不是TERT，限制了端粒酶的活性。
Telomerase consists of two essential components, the telomerase RNA template (TR) and telomerase reverse transcriptase (TERT). The haplo-insufficiency of TR was recently shown to cause one form of human dyskeratosis congenita, an inherited disease marked by abnormal telomere shortening. Consistent with this finding, we recently reported that mice heterozygous for inactivation of mouse TR exhibit a similar haplo-insufficiency and are deficient in the ability to elongate telomeres in vivo. To further assess the genetic regulation of telomerase activity, we have compared the abilities of TR-deficient and TERT-deficient mice to maintain or elongate telomeres in interspecies crosses. Homozygous TERT knockout mice had no telomerase activity and failed to maintain telomere length. In contrast, TERT+/- heterozygotes had no detectable defect in telomere elongation compared to wild-type controls, whereas TR+/- heterozygotes were deficient in telomere elongation. Levels of TERT mRNA in heterozygous mice were one-third to one-half the levels expressed in wild-type mice, similar to the reductions in telomerase RNA observed in TR heterozygotes. These findings indicate that both TR and TERT are essential for telomere maintenance and elongation but that gene copy number and transcriptional regulation of TR, but not TERT, are limiting for telomerase activity under the in vivo conditions analyzed.