Chromosomal fragile site

Silencing of the FMR1 gene in Fragile X syndrome. FMR1 co-localizes with a rare fragile site, visible here as a gap on the long arms of the X chromosome.

A chromosomal fragile site is a specific heritable point on a chromosome that tends to form a gap or constriction and may tend to break ^[1]when the cell is exposed to partial replication stress. ^[2] Based on their frequency, fragile sites are classified as "common" or "rare".^[3] To date, more than 120 fragile sites have been identified in the human genome.^[3][4]

Common fragile sites are considered part of normal chromosome structure and are present in all (or nearly all) individuals in a population. Under normal conditions, most common fragile sites are not especially prone to spontaneous breaks. Common fragile sites are of interest in cancer studies because they are frequently affected in cancer and they can be found in healthy individuals. Sites FRA3B (harboring the FHIT gene) and FRA16D (harboring the WWOX gene) are two well known examples and have been a major focus of research.

Rare fragile sites are found in less than 5% of the population, and are often composed of two- or three-nucleotide repeats. They are often susceptible to spontaneous breakage during replication, frequently affecting neighboring genes. Clinically, the most important rare fragile site is FRAXA, which is associated with the fragile X syndrome, the most common cause of hereditary mental retardation.

Fragile Sites and Affected Genes

FRA16D

• WWOX gene

FRAXA

FRBA3

• FHIT: Inactivates tumor suppressing ability
• C3orf14-Chromosome 3 open reading frame 14: Loss of gene expression

References

1. ^ Sutherland, GR and Hecht, F: Fragile Sites on Human Chromosomes. New York and Oxford: Oxford University Press, 280 pages (1985).
2. ^ Schwartz, M.; Zlotorynski, E.; Kerem, B. (2005), "The molecular basis of common and rare fragile sites", Cancer Letters 232 (1): 13–26, doi:10.1146/annurev.genet.41.042007.165900, PMID 17608616 
3. ^ ^{a b} Lukusa, T.; Fryns, J.P. (2008), "Human chromosome fragility", Biochimica et Biophysica Acta 1779 (1): 3–16, PMID 16236432 
4. ^ Durkin, S.G.; Glover, T.W. (2007), "Chromosome fragile sites", Annual Review of Genetics 41: 169–192, doi:10.1146/annurev.genet.41.042007.165900, PMID 17608616