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Chromosomal fragile site

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 when the cell is exposed to partial replication stress. Based on their frequency, fragile sites are classified as "common" or "rare". To date, more than 120 fragile sites have been identified in the human genome.

Rare fragile sites
Classification Rare fragile sites (RFSs) are classified into two sub-groups based on the compounds that elicit breakage: folate-sensitive groups (for examples, see ), and nonfolate-sensitive groups, which are induced by bromodeoxyuridine (BrdU) or distamycin A, an antibiotic that preferentially binds to AT-pairs of DNA. The folate-sensitive group is characterized by an expansion of CGG repeats, while the nonfolate-sensitive group contains many AT-rich minisatellite repeats. Mechanisms of instability The CGG and AT-rich repeats characteristic of RFSs can form hairpins and other non-B DNA structures that block replication forks and can result in breakage. DNA polymerase has been shown to pause at CTG and CGG triplet repeat sequences, which can result in continual expansion via slippage. ==Common fragile sites==
Common fragile sites
Classification Unlike RFSs, common fragile sites (CFSs) are not the result of nucleotide repeat expansion mutations. They are a part of the normal human genome and are typically stable when not under replicative stress. The majority of breakages at CFSs are induced by low doses of the antibiotic aphidicolin (APH). Co-treatment with low concentrations of the topoisomerase I inhibitor, camptothecin (CPT), reduces APH-induced breakage. CFS regions are highly conserved in mouse and other species, including primates, cat, dog, pig, horse, cow, Indian mole rat, and yeast (for review, see Mechanisms of instability The instability of CFSs is proposed to stem from late replication: CFSs are likely to initiate proper replication but slow to complete it, introducing breaks from unreplicated regions of DNA. Ataxia-telengiectasia and Rad3 Related (ATR) checkpoint kinase is required for maintaining stability of CFS under both stressed and normal replicating conditions. Breakage is reduced after treatment with CPT (camptothecin) (without APH), signifying that CPT also has a necessary role in stabilizing CFSs. ==Clinical relevance==
Clinical relevance
Fragile sites are associated with numerous disorders and diseases, both heritable and not. The FRAXA site is perhaps most famous for its role in Fragile X syndrome, but fragile sites are clinically implicated in many other important diseases, such as cancer. FRA3B and FRA16D lie within the large tumor-suppressor genes, FHIT and WWOX, respectively. High frequency of deletions at breakpoints within these fragile sites has been associated with many cancers, including breast, lung, and gastric cancers (for review, see Chromosomal alterations may lead to deregulation of microRNA, which could be of diagnostic and prognostic significance for cancers. Additionally, the Hepatitis B virus (HBV) and HPV-16 virus, the strain of human papilloma virus most likely to produce cancer, appear to integrate preferentially in or around fragile sites, and it has been proposed that this is crucial to the development of certain tumors. Fragile sites have also been implicated in a variety of syndromes (for a review, see ). For example, breakage at or near the FRA11b locus has been implicated in Jacobsen syndrome, which is characterized by loss of part of the long arm of chromosome 11 accompanied by mild intellectual disability. The FRAXE site is associated in the development of a form of intellectual disability without any distinctive phenotypic features. ==Fragile sites and affected genes==
Fragile sites and affected genes
• FRA1A • FRA1B (DAB1 gene) • FRA1C • FRA1D • FRA1E (DPYD gene) • FRA1F • FRA1G • FRA1H • FRA1I • FRA1J • FRA1K • FRA1L • FRA1M • FRA2A • FRA2B • FRA2C • FRA2D • FRA2E • FRA2F (LRP1B gene) • FRA2G • FRA2H • FRA2I • FRA2J • FRA2K • FRA2L • FRA3A • FRA3B (FHIT gene) • FRA3C (NAALADL2 gene) • FRA3D • FRA4A • FRA4B • FRA4C • FRA4D • FRA4E • FRA4F (GRID2 gene) • FRA5A • FRA5B • FRA5C • FRA5D • FRA5E • FRA5F • FRA5G • FRA5H (PDE4D gene) • FRA6A • FRA6B • FRA6C • FRA6D • FRA6E (PARK2 gene) • FRA6F • FRA6G • FRA6H • FRA7A • FRA7B • FRA7C • FRA7D • FRA7E • FRA7F • FRA7G • FRA7H • FRA7I (CNTNAP2 gene) • FRA7J • FRA7K (IMMP2L gene) • FRA8A • FRA8B • FRA8C • FRA8D • FRA8E • FRA8F • FRA9A • FRA9B • FRA9C • FRA9D • FRA9E • FRA9F • FRA9G • FRA10A • FRA10B • FRA10C • FRA10D (CTNNA3 gene) • FRA10E • FRA10F • FRA10G • FRA11A • FRA11B • FRA11C • FRA11D • FRA11E • FRA112F (DLG2 gene) • FRA11G • FRA11H • FRA11I • FRA12A • FRA12B • FRA12C • FRA12D • FRA12E • FRA13A (NBEA gene) • FRA13B • FRA13C • FRA13D • FRA13E • FRA14B (GPHN gene) • FRA14C • FRA15A (RORA gene) • FRA16A • FRA16B • FRA16C • FRA16D (WWOX gene) • FRA16E • FRA17A • FRA17B • FRA18A • FRA18B • FRA18C • FRA19A • FRA19B • FRA20A • FRA20B • FRA22A • FRA22B • FRAXB • FRAXC (IL1RAPL1/DMD genes) • FRAXD • FRAXA • FRAXE • FRAXF ==References==
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