Telomerase can't handle the stress

Abstract

Telomerase counteracts the telomere shortening that occurs with each round of cell division. In normal human cells, telomerase is repressed, leading to telomere shortening that triggers replicative senescence. However, in most tumors, telomerase is up-regulated and is essential for telomere maintenance and tumor cell growth. Although long considered a viable target for tumor therapy, successful inhibition of telomerase in cancer therapy remains to be described. In this issue of Genes & Development, Ahmed and Lingner (pp. 658-669) uncover a vulnerability in telomerase upon exposure of cancer cells to oxidative stress. It has long been known that telomeres are sensitive to damage by reactive oxygen species (ROS), but the impact of oxidation on telomerase function in living cells was not known. Using gene knockouts in colon cancer cells, the investigators demonstrate that the antioxidant enzyme peroxiredoxin 1 (PRDX1) and the nudix phosphohydrolase superfamily enzyme (MTH1) cooperate to retain, upon oxidative stress, telomeres in a telomerase-extendible state. Considering that cancer cells are more vulnerable to ROS than noncancer cells, this work may open new avenues targeting telomeres and telomerase in tumor cells.

Keywords: MTH1; PRDX1; aging; cellular senescence; oxidative stress; telomerase; telomeres.

Figure 1.

PRDX1 and MTH1 cooperate to prevent telomerase inhibition during oxidative stress. ROS oxidizes dGTP to 8-oxo dGTP. In the absence of MTH1, 8-oxo dGTP is not converted to 8-oxo dGMP. The resulting increase in the 8-oxo dGTP pool leads to frequent incorporation by telomerase and chain termination. The loss of PRDX1, which increases ROS-promoted oxidation of dGTP to 8-oxo dGTP, further exacerbates the effects of MTH1 loss. Together, these two enzyme pathways ensure that telomeres exposed to oxidative stress are maintained in a telomerase-extendable state.