ReviewCellular senescence, cancer and aging: the telomere connection
Section snippets
Telomeres
Telomeres are distinctive DNA-protein structures at the ends of linear chromosomes. Telomeres enable cells to distinguish a chromosome end from a double strand break (DSB) in the genomic DNA. DNA DSBs are potentially catastrophic lesions. If not repaired, DSBs are subject degradation. Even if they are repaired, DSBs can lead to loss of heterozygosity (if repaired by homologous recombination) or chromosomal deletions or translocations (if repaired by non-homologous end-joining). Thus, without a
Telomere length
The germ line is thought to maintain telomere lengths within species-specific limits by the balanced action of the enzyme telomerase and a variety telomere-associated proteins. Telomerase is a ribonucleoprotein complex that adds the telomeric repeat sequence directly to the single stranded 3′ telomeric overhang (Blackburn, 1992, Greider, 1996, Lingner and Cech, 1998, Nugent and Lundblad, 1998, Collins, 2000, McEachern et al., 2000). A number of telomere-associated proteins have been shown to
Cellular senescence
Normal cells generally respond to critically short (presumably dysfunctional) telomeres by undergoing cellular senescence — an irreversible arrest of cell proliferation, accompanied by changes in cell function (reviewed in Campisi et al., 1996). At least in mammals, the senescence response very likely evolved to suppress tumorigenesis, acting as a failsafe mechanism to prevent the proliferation of cells at risk for neoplastic transformation. Normal cells undergo a senescence arrest when faced
Implications for cancer
Several lines of evidence suggest that telomeres contribute to the initiation and progression of malignant tumors in several ways.
First, let us consider telomere dysfunction — whether caused by erosion due to cell proliferation, direct damage, or disruption due to defective telomere-associated proteins. As discussed above, dysfunctional telomeres can have three cellular outcomes — cellular senescence, cell death, or genomic instability. Genomic instability clearly predisposes cells to
Implications for aging
As noted earlier, the senescence response is complex, entailing not only an irreversible growth arrest, but also selected changes in differentiated functions. Among the most striking senescence-associated change in cell function is the secretion of factors that can alter the integrity, function and proliferative homeostasis of tissues (Campisi, 1996, Campisi, 2000). This senescence-associated secretory phenotype is particularly striking in fibroblasts, a major component and regulator of the
Summary
Telomeres cap the ends of linear chromosomes and are essential for preserving genomic integrity. The length and structure of telomeres are controlled by a variety of proteins, some of which function exclusively at the telomere, others of which also participate in DNA repair. In the absence of telomerase, telomeres shorten with each cell cycle, but it is likely that cells sense and respond to the integrity of the telomeric t loop or other telomeric structure, rather than telomere length per se.
References (120)
- et al.
Telomere shortening is associated with cell division in vitro and in vivo
Exp. Cell Res.
(1995) - et al.
Telomere shortening and tumor formation by mouse cells lacking telomerase RNA
Cell
(1997) - et al.
Genetic instability and Darwinian selection in tumours
Trends Cell Biol.
(1999) Replicative senescence: an old lives tale?
Cell
(1996)From cells to organisms: can we learn about aging from cells in culture?
Exp. Gerontol.
(2001)- et al.
p53 Deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis
Cell
(1999) Mammalian telomeres and telomerase
Curr. Opin. Cell Biol.
(2000)- et al.
Turning telomeres off and on
Curr. Opin. Cell Biol.
(2001) Replicative senescence in the immune system: impact of the Hayflick limit on T-cell function in the elderly
Am. J. Hum. Genet.
(1998)- et al.
Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta 2/3) cancer-prone mouse
Cell
(1999)