Kedde Martijn, le Sage Carlos, Duursma Anja, Zlotorynski Eitan, van Leeuwen Bart, Nijkamp Wouter, Beijersbergen Roderick, Agami Reuven
Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
J Biol Chem. 2006 Dec 29;281(52):40503-14. doi: 10.1074/jbc.M607676200. Epub 2006 Nov 10.
The human telomerase RNA (hTR), together with the telomerase reverse transcriptase, hTERT, constitute the core components of telomerase that is essential for telomere maintenance. While hTR is ubiquitously expressed, hTERT is normally restricted to germ cells and certain stem cells, but both are often deregulated during tumorigenesis. Here, we investigated the effects of changes in hTR cellular levels. Surprisingly, while inhibition of hTR expression triggers a rapid, telomerase-independent, growth arrest associated with p53 and CHK1 activation, its increased expression neutralizes activation of these pathways in response to genotoxic stress. These hTR effects are mediated through ATR and are sufficiently strong to impair ATR-mediated DNA-damage checkpoint responses. Furthermore, in response to low UV radiation, which activates ATR, endogenous hTR levels increase irrespective of telomerase status. Thus, we uncovered a novel, telomerase-independent, function of hTR that restrains ATR activity and participates in the recovery of cells from UV radiation.
人端粒酶RNA（hTR）与端粒酶逆转录酶hTERT共同构成端粒酶的核心成分，端粒酶对端粒维持至关重要。虽然hTR在全身广泛表达，但hTERT通常局限于生殖细胞和某些干细胞，不过在肿瘤发生过程中二者常常失调。在此，我们研究了hTR细胞水平变化的影响。令人惊讶的是，抑制hTR表达会引发一种快速的、不依赖端粒酶的生长停滞，这与p53和CHK1激活相关，而其表达增加会中和这些通路对基因毒性应激的激活反应。这些hTR效应是通过ATR介导的，且足够强大，足以损害ATR介导的DNA损伤检查点反应。此外，响应激活ATR的低剂量紫外线辐射，内源性hTR水平会升高，而与端粒酶状态无关。因此，我们发现了hTR一种新的、不依赖端粒酶的功能，即抑制ATR活性并参与细胞从紫外线辐射中的恢复。
