Mutant telomerase RNAs induce DNA damage and apoptosis via the TRF2-ATM pathway in telomerase-overexpressing primary fibroblasts

作者：Mahalingam Dashayini; Tay Ling L; Tan Wei H; Chai Juin H; Wang Xueying^*

来源：FEBS Journal, 2011, 278(19): 3724-3738.

DOI：10.1111/j.1742-4658.2011.08290.x

• apoptosis
• DNA damage
• IMR90
• MT-hTers
• telomerase

Mutant template human telomerase RNAs (MT-hTers) have been shown to induce apoptosis in various cancer cells with high telomerase activity. However, the mechanism by which MT-hTers inhibit the growth of cancer cells and their effects on normal cells remain unknown. To determine the effects of MT-hTers on normal cells, MT-hTer-47A and -AU5 were introduced into IMR90 lung fibroblasts, which have low telomerase levels. Growth of IMR90 cells after MT-hTers infection was not significantly impaired; however, similar treatments in telomerase-overexpressing IMR90 [ IMR90 wild-type (WT)hTERT] cells inhibited cell proliferation and induced apoptosis. Confocal microscopy showed that MT-hTers induced DNA damage foci (i.e. 53BP1 and gamma-H2AX) in IMR90 WThTERT cells. Microarray analysis revealed that GADD45 gamma was significantly elevated in MT-hTer-treated IMR90 WThTERT cells. MT-hTers also induced ATM phosphorylation at Ser1981 in IMR90 WThTERT cells, and western blot analysis revealed high levels of phosphorylated p53 after the down-regulation of cellular TRF2 expression in MT-hTer-treated IMR90 WThTERT cells. Taken together, we have shown that MT-hTers induce double-stranded DNA break-like damages in telomerase positive IMR90 WThTERT cells after phosphorylation of ATM and p53 via suppression of TRF2, which may eventually lead to apoptosis via elevation of GADD45 gamma.

• 出版日期2011-10