Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts

Zglinicki, Thomas von; Pilger, R; Sitte, Nicolle

doi:10.1016/s0891-5849(99)00207-5

Cited by 491 publications

(346 citation statements)

References 27 publications

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“…ROS, as induced by UVA radiation, are known to cause breaks in G-rich sequences (von Zglinicki et al, 2000). Actually, it was shown that telomeric DNA was 5 to 10-fold more assailable than nontelomeric DNA (Oikawa and Kawanishi, 1999).…”

Section: Discussionmentioning

confidence: 99%

UVA radiation causes DNA strand breaks, chromosomal aberrations and tumorigenic transformation in HaCaT skin keratinocytes

et al. 2008

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The role of UVA-radiation-the major fraction in sunlight-in human skin carcinogenesis is still elusive. We here report that different UVA exposure regime (4 Â 5 J/cm 2 per week or 1 Â 20 J/cm 2 per week) caused tumorigenic conversion (tumors in nude mice) of the HaCaT skin keratinocytes. While tumorigenicity was not associated with general telomere shortening, we found new chromosomal changes characteristic for each recultivated tumor. Since this suggested a nontelomere-dependent relationship between UVA irradiation and chromosomal aberrations, we investigated for alternate mechanisms of UVA-dependent genomic instability. Using the alkaline and neutral comet assay as well as c-H2AX foci formation on irradiated HaCaT cells (20-60 J/cm 2 ), we show a dosedependent and long lasting induction of DNA single and double (ds) strand breaks. Extending this to normal human skin keratinocytes, we demonstrate a comparable damage response and, additionally, a significant induction and maintenance of micronuclei (MN) with more acentric fragments (indicative of ds breaks) than entire chromosomes particularly 5 days post irradiation. Thus, physiologically relevant UVA doses cause long-lasting DNA strand breaks, a prerequisite for chromosomal aberration that most likely contribute to tumorigenic conversion of the HaCaT cells. Since normal keratinocytes responded similarly, UVA may likewise contribute to the complex karyotype characteristic for human skin carcinomas.

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Section: Discussionmentioning

confidence: 99%

UVA radiation causes DNA strand breaks, chromosomal aberrations and tumorigenic transformation in HaCaT skin keratinocytes

et al. 2008

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“…31 Thus, although we cannot rule out the possibility that telomere shortening occurred as a result of a remote proliferative burst in the ductal epithelium (perhaps during repeated episodes of injury and repair), it seems to be independent of ongoing proliferation. The genesis of telomere shortening in PanIN lesions remains a matter of speculation; postulated mechanisms include a role for reactive oxidant species, 32 or inactivation of one or more telomere-binding proteins that maintain telomere lengths, [33][34][35] and additional studies may be able to elucidate this issue further.…”

Section: Discussionmentioning

confidence: 99%

Telomere Shortening Is Nearly Universal in Pancreatic Intraepithelial Neoplasia

Heek

Meeker

Kern

et al. 2002

The American Journal of Pathology

317

211

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A multistep model of carcinogenesis has recently been proposed for pancreatic ductal adenocarcinomas. In this model, noninvasive precursor lesions in the pancreatic ductules accumulate genetic alterations in cancer-associated genes eventually leading to the development of an invasive cancer. The nomenclature for these precursor lesions has been standardized as pancreatic intraepithelial neoplasia or PanIN. Despite the substantial advances made in understanding the biology of invasive pancreatic adenocarcinomas, little is known about the initiating genetic events in the pancreatic ductal epithelium that facilitates its progression to cancer. Telomeres are distinctive structures at the ends of chromosomes that protect against chromosomal breakage-fusion-bridge cycles in dividing cells. Critically shortened telomeres can cause chromosomal instability, a sine qua non of most human epithelial cancers. Although evidence for telomeric dysfunction has been demonstrated in invasive pancreatic cancer, the onset of this phenomenon has not been elucidated in the context of noninvasive precursor lesions. We used a recently de- The 5-year survival rate of patients with ductal adenocarcinoma of the pancreas is 4%, one of the lowest of any neoplasm. Each year, nearly 29,000 patients are diagnosed with pancreatic cancer in the United States, and almost all will succumb to their disease.

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“…Several lines of evidence suggest that telomeres are especially susceptible to oxidative DNA damage [100,101], which may be the major source of DNA damage in mammalian organisms [102][103][104]. Finally, mutations that alter the expression or function of any of the telomere-associated proteins can also cause telomeres to malfunction.…”

Section: Mechanisms Of Telomere Disruptionmentioning

confidence: 99%

Cancer and aging: the importance of telomeres in genome maintenance

Rodier

Kim

Nijjar

et al. 2005

The International Journal of Biochemistry & Cell Biology

118

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Telomeres are the specialized DNA-protein structures that cap the ends of linear chromosomes, thereby protecting them from degradation and fusion by cellular DNA repair processes. In vertebrate cells, telomeres consist of several kilobase pairs of DNA having the sequence TTAGGG, a few hundred base pairs of single-stranded DNA at the 3' end of the telomeric DNA tract, and a host of proteins that organize the telomeric double and single stranded DNA into a protective structure.

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Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts

Cited by 491 publications

References 27 publications

UVA radiation causes DNA strand breaks, chromosomal aberrations and tumorigenic transformation in HaCaT skin keratinocytes

UVA radiation causes DNA strand breaks, chromosomal aberrations and tumorigenic transformation in HaCaT skin keratinocytes

Telomere Shortening Is Nearly Universal in Pancreatic Intraepithelial Neoplasia

Cancer and aging: the importance of telomeres in genome maintenance

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