Chromosomal instability

ITowever, most normal somatic cells lack telomerase. Consequently, upon every cycle of cell division when the cell replicates its DNA, about 50-nucleotide portions are lost from the end of each telomere. Thus, over time, the telomeres of somatic cells in animals become shorter and shorter, eventually leading to chromosome instability and cell death. This phenomenon has led some scientists to espouse a telomere theory of aging that implicates telomere shortening as the principal factor in cell, tissue, and even organism aging. Interestingly, cancer cells appear immortal because they continue to reproduce indefinitely. A survey of 20 different tumor types by Geron Corporation of Menlo Park, California, revealed that all contained telomerase activity. 

In patients with ataxia-telangiectasia, an autosomal recessive disease in humans resulting in the development of cerebellar ataxia and lymphoreticular neoplasms, there appears to exist an increased sensitivity to damage by x-ray. Patients with Fanconi s anemia, an autosomal recessive anemia characterized also by an increased frequency of cancer and by chromosomal instability, probably have defective repair of cross-linking damage. 

Kitayama Y, Igarashi H, Sugimura H. Amplification of FISH signals using intermittent microwave irradiation for analysis of chromosomal instability in gastric cancer. Mol. Pathol. 1999 52 357-359. 

Chromosomal instability and its relationship to other end points of genomic instability. Cancer Res. 57 5557-5563. 

S. cerevisiae aurora/IPllp, C. elegans aurora/AIR-2, and mammalian aurora B (also called AIM-1) phosphorylate H3 at Ser-10 and Ser-28 during mitosis [39 1] (Fig. 5). Protein phosphatase 1 removes the phosphate at these sites [39,42]. INCENP is bound to aurora B and is essential for the proper targeting of aurora B on the chromosomes [43-45]. INCENP and aurora B (AIM-1) are overexpressed in a variety of human cancers, including colorectal cancer [43,46]. Overexpression of aurora B (AIM-1) in CHE diploid fibroblasts leads to chromosomal instability, suggesting that aurora B overexpression may play a role in carcinogenesis [46]. INCENP/aurora B and H3 phosphorylation appear to be involved in assembly of mitotic chromosomes, but not mitotic chromosome compaction [44,47]. 

Figure 8. Increased chromosome instability in ubrlA S. cerevisiae (3). (a) Sectoring assay for the chromosome loss using the SUPJJ-marked YPH277 (UBRl) strain and its ubrlA derivative (see Methods), (b) Immunoblot analysis of...

Fig. 1. The tumor genome can be altered in many ways. CIN = chromosome instability MSI = mi-crosatellite instability.

Goel A, Nagasaka T, Arnold CN et al. The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology 2007 132 127-138. Swanton C, Tomlinson 1, Downward J. Chromosomal instability, colorectal cancer and taxane resistance. CeZ/Cyc/e 2006 5 818-823. 

The capacity to produce elevated levels of oxygen radicals probably induces the spontaneous chromosomal instability of Bloom s cells and is responsible for the high incidence of neoplasia in Bloom patients [421]. It should be noted that Emerit and Cerutti [422]... 

Chapters 11 and 31. Since cancers contain multiple mutations, they are complex diseases. However, many specific susceptibility loci are being located, including some for breast cancer (Box 11-D),392 prostate cancer,393 and familial adenomatous polyposis, a hereditary disease leading to colon cancer.388 394 Cancer has long been known to be associated with chromosome instability including deletion and insertion mutations at simple repeat sequences, frame-shift mutations,395 DNA breakage, translocation,396 and losses or gains of whole chromosomes 397... 

The second example of the use of the intermittent heating is for identifying centromeres in gastric cancer cells (Kitayama et al., 1999). A panel of 17 centromeric specific a-satellite probes was used for detecting chromosomal instability in these cells. The study of centromeres is important because chromosomal abnormalities are a well-known characteristic of human cancers. 

Xu GL, Bestor TH, Bourch his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Yiegas-Pequignot E. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 1999 402 187-191. 

The major disadvantages of these cultures are the accentuated chromosomal instability, the larger phenotype variation in relation to the donor tissue, and the disappearance of specific and characteristic tissue markers (Freshney, 1994). 

Rothmund-Thomson (Recql 4) proteins. The genes that encode these proteins are altered in human syndromes of the same name. Patients with these diseases are predisposed to different forms of cancer. Cell lines derived from patients with these diseases exhibit chromosome instability and accumulate abnormal replication intermediates. When these helicase proteins are studied in vitro, they can unwind Holliday junction-like structures. A characteristic of many proteins involved in homologous recombination is that they can be visualized as forming subnuclear structures in cells in response to DNA damage. This can be directly visualized using immunofluorescence and the structures that are formed are called foci (see Section 23.8.2). 

After having discussed the cell-cycle transitions and the major steps in cytokinesis, the controls, (checkpoints) that watch over cell-cycle transitions and arrest the cycle when a defect has been spotted will be discussed. These cell-cycle checkpoints are of great importance. Malfunctions of these controls result in reduced fidelity of the timing of the cell cycle. They cause chromosomal instabilities (CINs) and result in uncontrolled cellular proliferation, and eventually cancer (see ref. 31 and Part 4). 

Kadhim, M.A., Macdonald, D.A., Goodhead, D.T., Lorimore, S.A., Marsden, S.J., Wright, E.G. (1992). Transmission of chromosomal instability after plutonium alpha-particle irradiation. Nature 355 738 0. 

Durkin SG, Arlt ME, Hewlett NG, Glover TW. Depletion of CHKl, but not CHK2, induces chromosomal instability and breaks at common fragile sites. Oncogene 2006 25 4381-4388. 

Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, et al. 1992. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 11 1921 -29... 

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States, with about 5% of cases associated with inherited mutations linked to colon cancer syndromes. The molecular basis of sporadic and inherited CRC involves two distinct pathways, one of chromosomal instability and one associated with microsateUite mstabifity. The original model of chromosome instability proposed in 1990 to explain the pathogenesis of most sporadic tumors (-85%) has been further characterized to reveal a complex chain of events whereby normal colon fining (mucosa) is transformed... 

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