Telomere dysfunction: multiple paths to the same end

Abstract

The molecular cloning of telomerase and telomere components has enabled the analysis and precise manipulation of processes that regulate telomere length maintenance. In mammalian cells and in other organisms, we now recognize that disruption of telomere integrity via any one of a number of perturbations induces chromosome instability and the activation of DNA damage responses. Thus, telomere dysfunction may represent a physiological trigger of the DNA damage or apoptotic response in an analogous fashion to other genotoxic insults that introduce chromosome breaks. Initial studies in mice lacking the murine telomerase RNA and in cells expressing a dominant negative version of the telomere binding protein TRF2 revealed a strong p53-dependent response to telomere dysfunction. Yet, telomere dysfunction exhibits p53-independent e ects as well, an observation supported by p53-independent responses to telomere dysfunction in p53 mutant human tumor cell lines and mouse cells. As most tumors are compromised for p53 function, examination of this p53-independent response warrants closer attention. A better understanding of this p53-independent response may prove critical for determining the ultimate utility of telomerase inhibitors in the clinic. This review will summarize our current understanding of the molecular responses to telomere dysfunction in mammalian cells.

Estrogen deficiency reversibly induces telomere shortening in mouse granulosa cells and ovarian aging in vivo

“…This suggestion is supported by the significantly shortened telomeres observed in the granulosa cell compartment of ArKO mice ( Fig. 2 and 4), as telomere deregulation underpins cell proliferative lifespan (Harrington and Robinson, 2002;Blasco, 2007;Schoeftner and Blasco, 2009). Consistently, late-generation female telomerase-negative mTR −/− mice, which lack the RNA template for telomerase, are infertile and have smaller ovaries than their wild-type counterparts (Lee et al, 1998).…”

Progressive Loss of Malignant Behavior in Telomerase-Negative Tumorigenic Adrenocortical Cells and Restoration of Tumorigenicity by Human Telomerase Reverse Transcriptase

“…Fourth, crisis in telomerase-negative tumors differs in significant ways from the response of telomerase-positive cancers to chemotherapy, including therapy with anti-telomerase agents (21,22). Importantly, anti-telomerase therapy may in fact induce ALT in tumor cells (45).…”

“…Thus a direct demonstration that replicative senescence/crisis acts as a tumor suppressor mechanism in cells that naturally lack a telomere maintenance mechanism has not been provided. The effects of anti-telomerase and senescenceinducing therapies have been studied in telomerase-positive cancer cells (21)(22)(23)(24), but these observations are of senescence or crisis acting on cells that are already telomerase positive and therefore do not address the question of how replicative senescence/crisis may act as a mechanism to prevent tumor development. Presumably, if this process acts in the early part of the life span as a mechanism to prevent lethal cancers, it must act to stop the growth of a tumor before cells acquire telomerase activity and indefinite proliferative capacity.…”

Statins Enhance Migratory Capacity by Upregulation of the Telomere Repeat-Binding Factor TRF2 in Endothelial Progenitor Cells

“…Telomere dysfunction can occur because of the loss of TRF2, implying a role of telomere "uncapping" rather than telomere shortening. [21][22][23][24][25][26][27] Here, we demonstrate that statins delay premature senescence in cultivated EPCs independently of mean telomere length. Statin-enhanced migratory activity of EPCs also depends in part on the induction of the telomere-capping protein TRF2.…”