Fragile Sites—Cytogenetic Similarity with Molecular Diversity

The biological significance of chromosomal fragility is not easily generalized among fragile loci. Two of the rare fragile sites on the X chromosome are manifestations of disease (mental retardation)–producing dynamic mutations, whereas the third rare fragile site on this chromosome, FRAXF, is not found within any known gene and does not lead to any obvious phenotypic abnormality. The autosomal fragile sites of this type may be associated with transcriptional silencing of genes in which they might be located. Breakage at fragile sites may be capable of producing chromosomal deletion syndromes, as perhaps occurs when FRA11B breakage leads to Jacobsen syndrome (Jones et al. 1995xAssociation of a chromosome deletion syndrome with a fragile site within the proto-oncogene CBL2. Jones, C, Penny, L, Mattina, T, Yu, S, Baker, E, Voullaire, L, Langdon, WY et al. Nature. 1995; 376: 145–149Crossref | PubMedSee all References1995). It is of interest that none of the rare folate-sensitive fragile sites has been identified in species other than humans, yet repeats that are potentially capable of expansion to fragile sites have been identified in other species.Fragile sites are probably all associated with localized genomic instability; although this instability might lead only to the “gap” seen in cytogenetic preparations, it is also possible that the consequences are more significant. There is growing evidence that some common fragile sites predispose their surrounding region to the localized chromosomal instability seen in certain cancers. FRA3B is one such region of instability, and abnormal transcripts of the FHIT gene in which it is located are found in a range of tumor and normal cell types (Siprashvili et al. 1997xReplacement of FHIT in cancer cells suppresses tumorigenicity. Siprashvili, Z, Sozzi, G, Barnes, LD, McCue, P, Robinson, AK, Eryomin, V, Sard, L et al. Proc Natl Acad Sci USA. 1997; 94: 13771–13776Crossref | PubMed | Scopus (323)See all References1997; Carapeti et al. 1998xAberrant transcripts of the FHIT gene are expressed in normal and leukaemic haemopoietic cells. Carapeti, M, Aguiar, RC, Sill, H, Goldman, JM, and Cross, NC. Br J Cancer. 1998; 78: 601–605Crossref | PubMedSee all References1998; Otterson et al. 1998xProtein expression and functional analysis of the FHIT gene in human tumor cells. Otterson, GA, Xiao, GH, Geradts, J, Jin, F, Chen, WD, Niklinska, W, Kaye, FJ et al. J Natl Cancer Inst. 1998; 18: 426–432CrossrefSee all References1998). The human caveolin genes CAV1 and CAV2 are located in the vicinity of FRA7G, which is frequently deleted in human cancers (Engelman et al. 1998bxGenes encoding human caveolin-1 and -2 are co-localized to the D7S522 locus (7q31.1), a known fragile site (FRA7G) that is frequently deleted in human cancers. Engelman, JA, Zhang, XL, and Lisanti, MP. FEBS Lett. 1998b; 436: 403–410Abstract | Full Text | Full Text PDF | PubMed | Scopus (174)See all References1998b). Caveolin-1 has been shown to have a role in the anchorage-dependent inhibition of growth in NIH 3T3 cells (Galbiati et al. 1998xTargeted downregulation of caveolin-1 is sufficient to drive cell transformation and hyperactivate the p42/44 MAP kinase cascade. Galbiati, F, Volonte, D, Engelman, JA, Watanabe, G, Burk, R, Pestell, RG, and Lisanti, MP. EMBO J. 1998; 17: 6633–6648Crossref | PubMedSee all References1998). The caveolins are therefore candidates for the tumor-suppressor gene presumed to be located in the FRA7G region (Engelman et al. 1998axMolecular genetics of the calveolin gene family: implications for human cancers, diabetes, Alzheimer disease, and muscular dystrophy. Engelman, JA, Zhang, X, Galbiati, F, Volonte, D, Sotgia, F, Pestell, RG, Minetti, C et al. Am J Hum Genet. 1998a; 63: 1578–1587Abstract | Full Text | Full Text PDF | PubMed | Scopus (150)See all References1998a). By similar mechanisms, fragile sites may also lead to gene amplification in tumors. The noncompacted state of the DNA at fragile sites may also facilitate the integration of viruses into the genome.