Telomere Dysfunction Increases Mutation Rate and Genomic Instability

Hackett, Jennifer A.; Feldser, David M.; Greider, Carol W.

doi:10.1016/s0092-8674(01)00457-3

Cited by 351 publications

(373 citation statements)

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“…Telomere shortening has been demonstrated to induce a variety of genetic changes, including chromosome fusion at sites of shortened telomeres and recombination events, both of which contribute to genomic instability. 17,18,30 Shortened telomeres have been identified in a variety of invasive cancers and preinvasive lesions of the pancreas and prostate, and telomere shortening may be a critical early event in the development of epithelial neoplasms. 13,14,31,32 In addition to telomere shortening observed in dysplastic and carcinoma specimens, the majority of metaplastic lesions of the gallbladder in this study also demonstrated telomere shortening, supporting prior genetic evidence that metaplastic change in the gallbladder represents an early neoplastic alteration.…”

Section: Discussionmentioning

confidence: 99%

Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma

et al. 2006

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Biliary tract carcinoma, including carcinoma of the gallbladder, intrahepatic bile ducts (cholangiocarcinoma), and extrahepatic bile ducts, affects 7500 people in the United States annually, and has an overall 32% 5-year survival rate for disease limited to the mucosa, and a dismal 10% 5-year survival for more advanced disease. The identification of factors involved in the pathogenesis and progression of biliary tract carcinoma is critical for devising effective methods of screening and treatment. Recent evidence suggests that reduction of the length of telomeres, which normally help maintain chromosomal stability, may promote the development and progression of a variety of carcinomas. Using a novel, recently validated telomere fluorescence in situ hybridization method, we examined telomere length in normal and inflamed gallbladder epithelium, metaplasia and dysplasia of the gallbladder, and biliary tract carcinoma to determine whether telomere shortening is associated with neoplastic progression in the biliary tract. Although normal and inflamed gallbladder epithelium demonstrated uniform normal telomere lengths, over half of all metaplastic lesions demonstrated shortened telomeres, supporting prior evidence that metaplastic lesions of the gallbladder are pre-neoplastic. Dysplastic epithelium and invasive carcinomas demonstrated almost universally abnormally short telomeres, indicating that telomere shortening occurs at an early, preinvasive stage of cancer development. In addition, invasive adenocarcinoma of the biliary tract frequently demonstrated intratumoral heterogeneity of telomere lengths. We conclude that telomere shortening is a consistent and early finding in the development of biliary tract carcinoma.

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Section: Discussionmentioning

confidence: 99%

Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma

et al. 2006

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“…In the absence of telomerase and either the Rad51 or Rad59 recombination pathways or Tel1, there are more broken chromosomes that escape repair owing to overburdening of the existing recombination capacity by telomere maintenance, less telomere protection or both, resulting in increased GCR rates even though there is sufficient recombination to maintain telomeres. There are three potential sources of broken chromosomes: replication errors that escape repair 3,11 , dicentric chromosomes due to telomere-telomere fusion followed by breakage of the dicentric chromosomes 1,2,15,19 and degradation of chromosome ends by exonucleases such as Exo1 (ref. 20).…”

Section: E T T E R Smentioning

confidence: 99%

“…In the absence of either of the Rad51 or Rad59 recombination pathways or Tel1, there are either increased levels of broken chromosomes that escape repair, decreased telomere protection, or both such that increased GCRs occur. However, the telomeres may also fail to protect chromosomes from telomere-telomere fusions leading to breakagefusion-bridge cycles (BFB) 1,2,15,19 or exonuclease digestion 20 . The broken chromosomes are then joined to each other or to telomeres by NHEJ to yield GCRs.…”

Section: E T T E R Smentioning

confidence: 99%

Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast

Pennaneach

Kolodner

2004

Nat Genet

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In telomerase-deficient Saccharomyces cerevisiae, telomeres are maintained by recombination. Here we used a S. cerevisiae assay for characterizing gross chromosomal rearrangements (GCRs) to analyze genome instability in post-senescent telomerase-deficient cells. Telomerase-deficient tlc1 and est2 mutants did not have increased GCR rates, but their telomeres could be joined to other DNAs resulting in chromosome fusions. Inactivation of Tel1 or either the Rad51 or Rad59 recombination pathways in telomerase-deficient cells increased the GCR rate, even though telomeres were maintained. The GCRs were translocations and chromosome fusions formed by nonhomologous end joining. We observed chromosome fusions only in mutant strains expressing Rad51 and Rad55 or when Tel1 was inactivated. In contrast, inactivation of Mec1 resulted in more inversion translocations such as the isochromosomes seen in human tumors. These inversion translocations seemed to be formed by recombination after replication of broken chromosomes.Telomeres function in replication and maintenance of chromosome ends, to prevent DNA ends from being inappropriately joined to each other and to prevent chromosome ends from activating checkpoints 1,2 . Telomeres are maintained by telomerase, which consists of the Est2 catalytic subunit, the Tlc1 RNA and other subunits 2 .Telomere maintenance also requires other proteins. These include the Tel1 protein kinase that functions in telomere protection and length regulation and proteins such as Cdc13 and Ku that target telomerase to telomeres and protect telomeres from degradation 2 . Proteins such as Pif1 help regulate telomere length 3 and prevent telomerase from adding telomeres to broken DNAs 3,4 . In telomerase-deficient S. cerevisiae cells telomeres are maintained by recombination 5,6 . Most mammalian cells lack telomerase 7 and have a limited lifespan. Immortalization and cancer progression require increased telomere maintenance capacity, either through upregulation of telomerase activity 7 or through the alternative lengthening of telomere pathway 8 .Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast L E T T E R S 612VOLUME 36 | NUMBER 6 | JUNE 2004 NATURE GENETICS RDKY5233 is a tlc1∆ type II strain. Additional relevant GCR rates include the tlc1∆ type I strain, RDKY5232 (3.1 × 10 -10 (0.9)); lig4∆ strain, RDKY3641 (1.6 × 10 -9 (9); ref. 10); tel1∆ lig4∆ strain, RDKY5238 (4.2 × 10 -9 (12)); and tel1∆ lig4∆ est2∆ strain, RDKY5240 (3.5 × 10 -9 (10)). ND, not determined.

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“…This phenomenon, usually characteristic of radiation exposure (Seymour et al, 1986;Kadhim et al, 1992), resulted in a persistent reduction in clonogenic survival and increase in chromosome aberrations in the distant progeny of cells which appeared to have completely recovered from the exposure. Genomic instability induced by agents other than metals is influenced by telomerase including hTERT and/or telomeres in a number of species including yeast, plants, mice and cultured human cells (Sabatier et al, 1994;Blasco et al, 1997;Hackett et al, 2001;Cui et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Effects of hTERT on metal ion-induced genomic instability

et al. 2006

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There is currently a great interest in delayed chromosomal and other damaging effects of low-dose exposure to a variety of pollutants which appear collectively to act through induction of stress-response pathways related to oxidative stress and ageing. These have been studied mostly in the radiation field but evidence is accumulating that the mechanisms can also be triggered by chemicals, especially heavy metals. Humans are exposed to metals, including chromium (Cr) (VI) and vanadium (V) (V), from the environment, industry and surgical implants. Thus, the impact of low-dose stress responses may be larger than expected from individual toxicity projections. In this study, a short (24 h) exposure of human fibroblasts to low doses of Cr (VI) and V (V) caused both acute chromosome damage and genomic instability in the progeny of exposed cells for at least 30 days after exposure. Acutely, Cr (VI) caused chromatid breaks without aneuploidy while V (V) caused aneuploidy without chromatid breaks. The longerterm genomic instability was similar but depended on hTERT positivity. In telomerase-negative hTERTÀ cells, Cr (VI) and V (V) caused a long lasting and transmissible induction of dicentric chromosomes, nucleoplasmic bridges, micronuclei and aneuploidy. There was also a long term and transmissible reduction of clonogenic survival, with an increased b-galactosidase staining and apoptosis. This instability was not present in telomerasepositive hTERT þ cells. In contrast, in hTERT þ cells the metals caused a persistent induction of tetraploidy, which was not noted in hTERTÀ cells. The growth and survival of both metal-exposed hTERT þ and hTERTÀ cells differed if they were cultured at subconfluent levels or plated out as colonies. Genomic instability is considered to be a driving force towards cancer. This study suggests that the type of genomic instability in human cells may depend critically on whether they are telomerase-positive or -negative and that their sensitivities to metals could depend on whether they are clustered or diffuse.

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Telomere Dysfunction Increases Mutation Rate and Genomic Instability

Cited by 351 publications

References 44 publications

Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma

Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma

Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast

Effects of hTERT on metal ion-induced genomic instability

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