Chromosome Fragility

Trinucleotide Repeat Expansion DNA region comprised of a variable number of repetitive, contiguous trinucleotide sequences. The presence of these regions is associated with diseases such as Fragile X Syndrome and myotonic dystrophy. Many chromosome fragile sites (chromosome fragility) contain expanded trinucleotide repeats, [nih]... 

Usdin, K. and Woodford, K.J. (1995) CGG repeats associated with DNA instability and chromosome fragility form structures that block DNA synthesis in vitro. Nucl Acids Res 23 4202-4209. 

Autosomal recessive-inherited cancer syndromes associated with chromosome fragility or decreased DNA repair predisposes affected individuals to cancer. 

Another situation favoring selection of dormant tumor cells occurs in immunodeficiency states. Spontaneous or induced immunodeficiency often increases susceptibility to neoplasia (Kl, M3). However, the results show more variability than can be explained simply by impairment of immunologic surveillance (M3). In humans the excess is largely due to an increase in the frequency of leukemias and lymphomas, except in those immunodeficiency states associated with chromosomal fragility, such as ataxia telangiectasia (P2, S10). 

Slone, D. M..and Stephens, K. E. (1993). Animal model—Bromodeoxyuridine induces chromosomal fragile sites in the canine genome. Am. J. Med. Genet. 46, 198-202. 

SURRALLES J, PUERTO S, RAMIREZ MI, CREUS A, MARCOS R, MULLENDERS L H and NATA-RAJAN A T (1998) Links between chromatin structure, DNA repair and chromosome fragility. Mutat Res, 404, 39-44. 

The genetic information of eukaryotic cells is propagated in the form of chromosomal DNA. Besides the nucleic acid component, chromosomes contain architectural proteins as stoichiometric components, which are involved in the protective compaction of the fragile DNA double strands. Together, the DNA and proteins form a nucleoprotein structure called chromatin. The fundamental repeating unit of chromatin is the nucleosome core particle. It consists of about 147 base pairs of DNA wrapped around a histone octamer of a (H3/H4)2 tetramer and two (H2A-H2B) heterodimers. One molecule of the linker histone HI (or H5) binds the linker DNA region between two nucleosome core particles (Bates and Thomas 1981). 

Fragile X syndrome is the leading inherited cause of mental retardation in humans. It affects about 1 out of 2000 males and about 1 out of 4000 females. The degree of mental retardation is quite variable, from a mild mental impairment to severe mental retardation. The disease is frequently more serious in males than females males have only the defective X chromosome, whereas females have one normal X chromosome to go along with the defective one. There is no specific treatment for Fragile X syndrome. 

X-hnked dominant disorders are caused by fragile X mutations in genes on the X chromosome, syndrome Females are more frequently affected than males, and the chance of passing on an X-hnked dominant disorder differs between men and women. Families with an X-hnked dominant disorder often have both affected males and affected females in each generation. A striking characteristic of X-hnked inheritance is that fathers cannot pass X-hnked traits to their sons (no male-to-male transmission). 

Figure 1-3. Partial karyotypes of Giemsa-stained human chromosomes showing various manifestations of the fragile X site (arrows) a chromatid break (a), an isochromatid gap (b), a chromosome break (c), and endoreduplication (d).

Sutherland GR Fragile sites on human chromosomes demonstration of their dependence on the type tissue culture medium. Science 197 265-266,1977. 

The diseases and disorders chosen for discussion and the order of presentation parallel subject matter taught in most first-year medical biochemistry. Chapters in the first part of the book, Nucleic Acids and Protein Structure, illustrate the relationships of protein structure and function with respect to collagen (Osteogenesis Imperfecta) and hemoglobin (Sickle Cell Anemia). The chapters Fragile X Syndrome and Hereditary Spherocytosis discuss key aspects of DNA and protein structure and their respective role in chromosomal and cytoskeletal structure. The chapter cardiac troponin and myocardial infarction provides an up-to-date demonstration of the usefulness of both structural proteins and enzymes as markers of cardiovascular disease, while the chapter cx Anti trypsin Deficiency discusses the important role of endogenous enzyme inhibitors. 

This boy has a sex-linked chromosomal defect, known as fragile-X, that can cause mental retardation and other symptoms. Doctors are treating fragile-X syndrome children successfully with experimental drugs. 

At least nine fragile sites are present in human chromosomes. The fragility refers to chromosomal sites that break easily in the presence of certain compounds such as aphidocolin, methotrexate, and high doses of caffeine (Sutherland, 1979a, b). These sites are generally (GCC) stretches and in most cases are protected if folate, thymidine, or folinic acid is in the medium (Sutherland, 1979a, b,... 

Sutherland GR (1979a) Heritable fragile sites on human chromosomes. I. Factors affecting expression in lymphocyte culture. Am J Hum Genet 31 125-135... 

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. 

El Achkar E, Gerbault-Seureau M, Muleris M, Dutrillaux B, Debatisse M. Premature condensation induces breaks at the interface of early and late replicating chromosome bands bearing common fragile sites. Proc. Natl. Acad. Sci. U.S.A. 2005 102 18069-18074. 

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