Telomeres — the structures at the end of chromosomes — have a long history in biogerontology. Telomeres shorten with every cell division, essentially providing a “clock” that ticks down until reaching some critical length, at which point the cell will undergo the permanent growth arrest known as senescence. Even though this clock is an important tumor suppression checkpoint (because it prevents cells that have divided many times from continuing to proliferate), senescent cells themselves contribute both directly and indirectly to aging (by diminishing regenerative capacity and secreting deleterious signaling molecules, respectively). Telomere length is also a useful biomarker: it is positively correlated with life expectancy, and appears to respond to environmental influences including chronic infection and psychological stress.
Telomeres and telomerase are therefore subjects of a great deal of active study, and if one isn’t careful one can quickly fall far behind the literature — as I have. Keeping up with the pace I set yesterday, then, here are a few of the many worthy telomere papers published over the past few months. Quoted passages are excerpts from the articles’ abstracts.
Senescence and its transcriptional profile: Telomere dysfunction in human keratinocytes elicits senescence and a novel transcription profile, Minty et al.:
Transcriptional profiling of TRF2-depleted keratinocytes showed a reproducible up-regulation of several genes. … This study has thus revealed highly sensitive and specific candidate indicators of telomere dysfunction that may find use in identifying telomere-mediated keratinocyte senescence in ageing, cancer and other diseases.
Telomere clocks and biological clocks: Telomerase reconstitution contributes to resetting of circadian rhythm in fibroblasts, Qu et al.:
We found that the response of rhythmic gene expression to serum stimulation was markedly attenuated in senescent fibroblasts, telomerase-reconstituted fibroblasts reset the circadian oscillation of rhythmic gene expression … These findings suggested that telomerase reconstitution might be a good way to reset synchronization of peripheral circadian rhythms disrupted in senescent tissues.
Telomere dysfunction and progeria: Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita, Vulliamy et al.:
Dyskeratosis congenita is a premature aging syndrome characterized by muco-cutaneous features and a range of other abnormalities, including early greying, dental loss, osteoporosis, and malignancy. … Most of the mutations so far identified in patients with classical dyskeratosis congenita impact either directly or indirectly on the stability of RNAs. In keeping with this effect, patients with dyskerin, NOP10, and now NHP2 mutations have all been shown to have low levels of telomerase RNA in their peripheral blood, providing direct evidence of their role in telomere maintenance in humans.
Cancer prevention: Telomere dysfunction and tumour suppression: the senescence connection, Deng et al.:
Impaired telomere function activates the canonical DNA damage response pathway that engages p53 to initiate apoptosis or replicative senescence. Here, we discuss how p53-dependent senescence induced by dysfunctional telomeres may be as potent as apoptosis in suppressing tumorigenesis in vivo.
Cirrhosis and senescence: Telomere shortening in the damaged small bile ducts in primary biliary cirrhosis reflects ongoing cellular senescence, Sasaki et al.:
Telomere shortening and an accumulation of DNA damage coincide with increased expression of p16INK4a and p21WAF1/Cip1 in the damaged bile ducts, characterize biliary cellular senescence, and may play a role in the following progressive bile duct loss in PBC.
Telomere length in schizophrenia: Short telomeres in patients with chronic schizophrenia
who show a poor response to treatment, Yu et al.:
Compared with the control group, a significant amount of telomere shortening was found in peripheral blood leukocytes from patients with schizophrenia who experienced poor response to antipsychotics (p< 0.001). Conclusion: Shortened telomere length in chronic schizophrenia may be a trait marker caused by oxidative stress, and the ensuing cellular dysfunction may be a factor contributing to the progressive deterioration in treatment-resistant schizophrenia.
And finally, two articles about the growing body of evidence that telomerase has functions other than making new telomeres:
Moonlighting, reviewed: Actions of human telomerase beyond telomeres, Cong and Shay:
…recent studies have led some investigators to suggest novel biochemical properties of telomerase in several essential cell signaling pathways without apparent involvement of its well established function in telomere maintenance. … This review will provide an update on the extracurricular activities of telomerase in apoptosis, DNA repair, stem cell function, and in the regulation of gene expression.
What’s going on in the nucleolus?: Nucleolar localization of TERT is unrelated to telomerase function in human cells, Lin et al.:
Here, we identify that residues 965-981 of the human TERT polypeptide constitute an active nucleolar-targeting signal (NTS) essential for mediating human TERT nucleolar localization. Mutational inactivation of this NTS completely disrupted TERT nucleolar translocation in both normal and malignant human cells. Most interestingly, such a TERT mutant still retained the capacity to activate telomerase activity, maintain telomere length and extend the life-span of cellular proliferation, as does wild-type TERT, in BJ cells (normal fibroblasts).
Tomorrow: protein degradation and, if I get to it, oxidation.