Article

Telomere Loss as a Mechanism for Chromosome Instability in Human Cancer

Department of Radiation Oncology, University of California San Francisco, San Francisco, CA 94143-1331, USA.
Cancer Research (Impact Factor: 9.28). 06/2010; 70(11):4255-9. DOI: 10.1158/0008-5472.CAN-09-4357
Source: PubMed

ABSTRACT Cancer cells commonly have a high rate of telomere loss, even when expressing telomerase, contributing to chromosome instability and tumor cell progression. This review addresses the hypothesis that this high rate of telomere loss results from a combination of four factors. The first factor is an increase in the frequency of double-strand breaks (DSB) at fragile sites in cancer cells due to replication stress. The second factor is that telomeres are fragile sites. The third factor is that subtelomeric regions are highly sensitive to DSBs, so that DSBs near telomeres have an increased probability of resulting in chromosome instability. The fourth factor is that cancer cells may be deficient in chromosome healing, the de novo addition of telomeres to the sites of DSBs, a mechanism that prevents chromosome instability resulting from DSBs near telomeres. Understanding these factors and how they influence telomere loss will provide important insights into the mechanisms of chromosome instability and the development of novel approaches for anti-cancer therapy. Cancer Res; 70(11); 4255-9. (c)2010 AACR.

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    • "Counter et al. [24] demonstrated that transfecting human fibroblasts with viral proteins led to the inactivation of p53 and p16 pathways. Deficiency of p53/p16 proteins leads to ''crisis'' which is characterized by a high rate of telomere loss and instability in chromosome structure [25] [26] [27] [28]. Crisis serves as another line of defense against the development of cancer because the resulting genome instability and DNA-damage signaling induce the death of the vast majority of cells. "
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    • "Telomeres are repetitive structures at the end of chromosomes that are essential for maintaining and protecting the chromosomes from degradation and end-to-end fusion [1] [2]. Many studies suggest that the loss of telomere function leads to genomic instability [3] [4] [5] [6] [7]. "
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    • "In human somatic cells, telomeres shorten which are attributed to down-regulation of telomerase, causes chromosome fusions lossing, cell cycle arrest and apoptosis. However, telomerase are active in more than 85% of cancer tumors (Murnane, 2010). These findings imply that activation of telomerase is associated with the development of cancer tumors (Donate & Blasco, 2011). "
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