Telomere dynamics, aging, and cancer: Study of human syndromes characteristic of premature aging

Asha S. Multani, Satya Narayan, Aruna S. Jaiswal, Yi Jue Zhao, Ruth A. Barkley, Cynthia L. Furlong, Sen Pathak

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Age-related reduction of telomeric DNA sequences contributes to mitotic catastrophe and genetic instability, which in turn play major roles in the increased risk of developing cancer. Human B-cells from patients with Fanconi's anemia (FA), ataxia-telangiectasia (AT), Bloom syndrome (BS), and xeroderma pigmentosum (XP) syndromes, causing premature aging and predisposition to neoplasia, were studied for telomere dynamics and mitotic catastrophe, including the frequency of endoreduplication and structural abnormalities. We hypothesized that somatic cells affected by these syndromes have shortened telomeres and down-regulation of telomere repeat binding factor 2 (TRF2). Using conventional and molecular cytogenetic techniques such as quantitative fluorescence in situ hybridization (Q-FISH), we compared patients' cells to cells from age- and sex-matched individuals. The frequency of metaphases with mitotic catastrophe and telomeric associations was significantly higher in FA, BS, and AT cells than in controls, XP being within normal limits. All B-cells (patients and controls) were telomerase positive. Q-FISH showed less telomeric DNA in patient cells compared with controls. However, one control also showed reduced telomeric DNA and increased mitotic catastrophe, with XP cells showing decreased aberrations compared to other syndromes. Western blot analysis of TRF2 showed reduced levels in AT, BS, FA, and one control group. XP cells showed levels of TRF2 protein, similar to controls. From this, we conclude that genetic instability is caused by loss of telomeric DNA. A reduction of telomeric DNA is, therefore, responsible for genetic instability and could be an important factor in causation of or predisposition to develop cancer in these syndromes.

Original languageEnglish (US)
Pages (from-to)271-281
Number of pages11
JournalJournal of anti-aging medicine
Volume5
Issue number3
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Aging

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