New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin

Abstract

Telomeres are stabilized, and telomeric DNA is replenished, by the action of the ribonucleoprotein reverse transcriptase telomerase. Telomere capping functions include the ability of telomeres to protect chromosome ends from cellular DNA-damage responses such as cell cycle arrest or apoptosis. This property of telomeres is especially important for cancer cells, which continue proliferating despite chromosome aberrations. Telomere capping is in¯uenced by multiple, mutually reinforcing factors including telomere length, although telomere length is only one of several determinants of telomere functionality. For example, many cancer cells express high levels of telomerase yet maintain relatively short telomeres. We consider three aspects of telomere capping that have emerged relatively recently: (1) a new role for telomerase in telomere capping independent of its function in telomere elongation. Support for this novel function comes from experiments showing an increase in replicative potential with the reactivation of telomerase, without net telomere lengthening; (2) the role at telomeres of DNA damage proteins. We propose a model in which two factors speci®cally target telomeres for the action of telomerase, as opposed to recombination or non-homologous end-joining: binding by telomeric proteins that limits DNA damage responses at telomeres, and the a nity of the telomerase RNP for telomeric proteins and DNA; and (3) we discuss a potential protective role of ampli®ed subtelomeric DNAs, which may aid capping of telomeres maintained by nontelomerase based mechanisms through the formation of heterochromatin.

Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines

“…Shortening of telomeres as a result of different telomerase inhibitors leading to cellular senescence and apoptosis has been demonstrated in several reports (Hahn et al, 1999;Herbert et al, 1999Herbert et al, , 2002Izbicka et al, 1999;Damm et al, 2001;Boklan et al, 2002;Grand et al, 2002;Seimiya et al, 2002;Pang et al, 2003). The other protective function of telomerase, proposed by Blackburn and her group, was named 'telomeres capping' (Chan and Blackburn, 2002). A concomitant inhibition of telomerase and alteration in the expression of AKT 1 and PP2A were detected 24 h following IM treatment.…”

Cancer and aging: the importance of telomeres in genome maintenance

“…1). Because telomeres enable cells to distinguish the chromosome ends from intrachromosomal double stranded breaks (DSBs), dysfunctional or uncapped chromosome ends are at great risk for degradation, recombination, and/or fusion by cellular DNA repair systems such as non-homologous DNA end-joining (NHEJ) [29,30]. Telomeric fusions create dicentric chromosomes, which can break during mitosis, thereby creating bona fide DSBs, cycles of chromosome bridges, breakage and fusions, and ultimately genomic rearrangements in the surviving cells [31].…”

Telomeres and telomerase

“…B (2004) yeast is dedicated largely to telomere maintenance; in humans, defective ATM leads to telomere fusions and cancer susceptibility. Ku, a protein needed for DNA end joining of broken DNA, is also required for normal telomere maintenance by telomerase (reviewed in Chan & Blackburn 2002).…”