Murnane JP, Sabatier LChromosome rearrangements resulting from telomere dysfunction and their role in cancer. BioEssays 26: 1164-1174
Radiation Oncology Research Laboratory, University of California, San Francisco, CA 94103, USA. BioEssays
(Impact Factor: 4.73).
11/2004; 26(11):1164-74. DOI: 10.1002/bies.20125
Telomeres play a vital role in protecting the ends of chromosomes and preventing chromosome fusion. The failure of cancer cells to properly maintain telomeres can be an important source of the chromosome instability involved in cancer cell progression. Telomere loss results in sister chromatid fusion and prolonged breakage/fusion/bridge (B/F/B) cycles, leading to extensive DNA amplification and large deletions. These B/F/B cycles end primarily when the unstable chromosome acquires a new telomere by translocation of the ends of other chromosomes. Many of these translocations are nonreciprocal, resulting in the loss of the telomere from the donor chromosome, providing a mechanism for transfer of instability from one chromosome to another until a chromosome acquires a telomere by a mechanism other than nonreciprocal translocation. B/F/B cycles can also result in other forms of chromosome rearrangements, including double-minute chromosomes and large duplications. Thus, the loss of a single telomere can result in instability in multiple chromosomes, and generate many of the types of rearrangements commonly associated with human cancer.
Available from: Celine Mirjolet
- "Indeed, there is a higher incidence of certain tumors in telomerase-Knock-Out (KO) mice that harbor p53 mutations  . Sabatier et al. showed that a single telomere loss can lead to multiple telomere dysfunctions , and several studies have shown that telomere dysfunction was responsible for genomic instability leading to cancer  . More recently, two studies have demonstrated the implication of telomere dysfunction in triggering aggressive tumors. "
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ABSTRACT: Radiotherapy plays a key role in cancer treatments, but tumor cell death differs from one tumor to another. The response of patients to radiotherapy varies considerably and adverse side effects are difficult to prevent. The mechanisms involved in the heterogeneity of this response are not well understood. In order to enhance the efficacy and safety of radiotherapy, it is important to identify subpopulations most at risk of developing a late adverse response to radiotherapy. Telomeres are composed of multiple repeats of a unique sequence of nucleotides forming a TTAGGG pattern. They protect chromosomes from end-to-end fusion and maintain genomic stability. Telomeres have been shown to be extremely sensitive to radiotherapy especially because of their atypical DNA damage repair response, which includes partial inhibition of the non-homologous end joining repair pathway. Ionizing Radiation (IR)-induced damage to telomere DNA could lead to chromosome instability and the initiation or progression of tumor processes. Telomeres could thus be a reliable marker of IR exposure and as such become a new parameter for predicting radiosensitivity. Furthermore, short telomeres are more sensitive to radiotherapy, which could partially explain differences in tumor cell death and in inter-individual sensitivity to radiotherapy. Telomere length could be used to identify subpopulations of patients who could benefit from higher or lower doses per fraction. Finally, pharmacological interference with tumor-cell telomere biology to reduce telomere length and/or telomere stability could also enhance the effectiveness and safety of radiotherapy. Telomeres could play a key role in radiotherapy in the era of personalized medicine.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Available from: genesdev.cshlp.org
- "One is centromere inactivation through DNA rearrangements or epigenetic switches at one centromere (Lejeune et al. 1973; Avarello et al. 1992; Kramer et al. 1994; Pennaneach and Kolodner 2009; Mackinnon and Campbell 2011; Sato et al. 2012; Song et al. 2013). The other is telomere addition at the broken ends; for instance, by telomerase or break-induced replication (Murnane and Sabatier 2004; Pennaneach and Kolodner 2009). "
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ABSTRACT: Dicentric chromosomes are unstable products of erroneous DNA repair events that can lead to further genome rearrangements and extended gene copy number variations. During mitosis, they form anaphase bridges, resulting in chromosome breakage by an unknown mechanism. In budding yeast, dicentrics generated by telomere fusion break at the fusion, a process that restores the parental karyotype and protects cells from rare accidental telomere fusion. Here, we observed that dicentrics lacking telomere fusion preferentially break within a 25- to 30-kb-long region next to the centromeres. In all cases, dicentric breakage requires anaphase exit, ruling out stretching by the elongated mitotic spindle as the cause of breakage. Instead, breakage requires cytokinesis. In the presence of dicentrics, the cytokinetic septa pinch the nucleus, suggesting that dicentrics are severed after actomyosin ring contraction. At this time, centromeres and spindle pole bodies relocate to the bud neck, explaining how cytokinesis can sever dicentrics near centromeres.
© 2015 Lopez et al.; Published by Cold Spring Harbor Laboratory Press.
Available from: Marin Mladinic
- "Among the various environmental factors affecting telomere maintenance, chemical exposure has been detected but insufficiently studied. Many studies have shown that the attrition of telomeres leads to genomic instability associated with various age-related disorders including cancers (Murnane and Sabatier, 2004). Certain types of cancer proven to have short telomeres such as non-Hodgkin's lymphoma , leukemia, brain, breast, kidney, and prostate cancer have been linked with pesticide exposure (Bassil et al., 2007). "
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ABSTRACT: Agricultural workers are often exposed to high levels of pesticides over prolonged periods of time. We attempted to determine whether exposure to multiple pesticides shortens relative telomere length (RTL) and causes nucleoplasmic bridge (NPB) formation via the mechanism of telomere-end fusion in the lymphocytes of agricultural workers. For measuring RTL, we used quantitative fluorescent in situ hybridization, while NPB frequency was measured as part of the cytome assay. Multivariate analysis of variances taking into account confounding factors (age, gender, years of exposure, smoking, and alcohol intake) did not show a decrease, but rather an increase of RTL in agricultural workers compared to control individuals. In the exposed population, NPB frequency was significantly higher compared to controls (6 times, p<0.05). Multiple regression between NPB, RTL, and confounding factors was not significant. Using Spearman correlation, we did not find proof for our initial hypothesis. Our hypothesis that telomere shortening is a mechanism of NPB origin was not proven, indicating that telomere-end fusion is not a mechanism of NPB formation under our experimental conditions for agricultural workers.
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