Telomerase Suppresses Formation of ALT-Associated Single-Stranded Telomeric C-Circles

Abstract

Telomere maintenance is an essential characteristic of cancer cells, most commonly achieved by activation of telomerase. Telomeres can also be maintained by a recombination-based mechanism, alternative lengthening of telomeres (ALT). Cells using ALT are characterized by the presence of ALT-associated promyelocytic leukemia (PML) bodies (APB), long, heterogeneously sized telomeres, extrachromosomal telomeric circular DNA, and elevated telomeric recombination. Consistent with other reports, we found that liposarcomas containing APBs, but lacking telomerase expression, always contained C-rich circles (C-circles), and these C-circles were never present in the absence of APBs, indicating a tight link between these features in ALT cells. However, a rare subgroup of tumors showing evidence of telomere maintenance by both telomerase and ALT did not contain C-circles. To test the hypothesis that telomerase expression disrupts the tight link between APBs and C-circles, we used ALT cell lines that were engineered to express telomerase. Introduction of telomerase activity in these ALT cells resulted in, on average, shorter telomeres with retention of APBs. However, at high passage, the level of C-circles was significantly reduced, which was paralleled by a switch from C-strand overhangs to G-strand overhangs. We propose that by extending critically short telomeres in these cells, telomerase is disrupting a key step in the ALT pathway necessary for production and/or maintenance of C-circles. Mol Cancer Res; 11(6); 557-67. Ó2013 AACR.

Implications of TERT promoter mutations and telomerase activity in urothelial carcinogenesis

“…Recurrent mutations in the death-associated protein (DAXX) and the alphathalassemia X-linked protein (ATRX) have been correlated with ALT occurrence and potentially contribute to ALT maintenance 33,34 . Of note, there is evidence that telomerase activity supresses ALT, although the suppressive mechanism is yet to be identified [34][35][36][37][38][39][40][41][42][43][44][45][46][47] . In a comprehensive analysis of 6,110 human tumour specimens from various cancer types, ALT was observed in only ~4% of samples 48 .…”

Telomere Biology—Insights into an Intriguing Phenomenon

“…The interplay between ALT and telomerase-mediated elongation, and their effect on telomere homeostasis is yet to be brought to light, although there have been observations of their coexistence in normal mouse somatic cells and human tumour samples recently [117,118,119]. Emerging evidence points to the localisation of telomeres as a compelling drive in determining the mechanism of maintenance.…”

Decreased expression of TERT correlated with postnatal cochlear development and proliferation reduction of cochlear progenitor cells

“…Most eukaryocyte somatic cells have undetectable telomerase activity due to transcriptional repression of the catalytic subunit TERT during the early stage of embryo development, but its expression is limited to highly proliferative tissues, such as germ cells and stem cells after birth. Several studies have proved that TERT is critical for maintaining the capability of stem cells and promoting cell proliferation (18)(19)(20)(21)(22)(23)(24).…”