New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin.
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 influenced 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 specifically 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 affinity of the telomerase RNP for telomeric proteins and DNA; and (3) we discuss a potential protective role of amplified subtelomeric DNAs, which may aid capping of telomeres maintained by non-telomerase based mechanisms through the formation of heterochromatin.
Chan
Simon W-L
SW
Department of Biochemistry and Biophysics, University of California, San Francisco, California, CA 94143-0448, USA.
Blackburn
Elizabeth H
EH
D000818:Animals; D002455:Cell Division; D004249:DNA Damage; D006570:Heterochromatin / Q000502:physiology; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics; D009687:Nuclear Proteins / Q000502:physiology*; D019098:Telomerase / Q000502:physiology*; D016615:Telomere / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
D006570:Heterochromatin; D009687:Nuclear Proteins; D019098:Telomerase