Chromosomal Fragile Site

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2021-01-18

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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 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.

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 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 intellectual disability. For detailed information regarding each characterized fragile site, please visit HumCFS: a database of fragile sites in human chromosomes, published in BMC Genomics.

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

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 aphidocilin (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 ). While CFSs could be a result of higher-order chromosome structure, the conservation throughout species could also indicate that they may have some conserved biological purpose.

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. Late-replication may be a result of formation of non-B DNA structures like hairpins and toroids that stall the replication fork in AT rich regions, analogous to the proposed mechanism of rare fragile site instability. 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

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 ) MicroRNA genes, which are preferentially involved in chromosomal alterations, are frequently located at fragile sites. 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 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 mental retardation. The FRAXE site is associated in the development of a form of mental retardation without any distinctive phenotypic features. Seckel syndrome, a genetic disease characterized by low levels of ATR, results in increased instability of chromosomes at fragile sites.

Chromosomal Fragile Site

Rare Fragile Sites

Classification

Mechanisms of Instability

Common Fragile Sites

Classification

Mechanisms of Instability

Clinical Relevance

Fragile Sites and Affected Genes

FRA1A

FRA1B

FRA1C

FRA1D

FRA1M

FRA1E

FRA1J

FRA1F

FRA1G

FRA1K

FRA1L

FRA1H

FRA1I

FRA2C

FRA2D

FRA2E

FRA2L

FRA2A

FRA2B

FRA2F

FRA2K

FRA2G

FRA2H

FRA2I

FRA2J

FRA3A

FRA3B

FRA3D

FRA3C

FRA4A

FRA4D

FRA4B

FRA4F

FRA4E

FRA4C

FRA5E

FRA5A

FRA5H

FRA5D

FRA5B

FRA5F

FRA5C

FRA5G

FRA6B

FRA6A

FRA6C

FRA6H

FRA6D

FRA6G

FRA6F

FRA6E

FRA7B

FRA7C

FRA7D

FRA7A

FRA7J

FRA7E

FRA7F

FRA7K

FRA7G

FRA7H

FRA7I

FRA8F

FRA8B

FRA8A

FRA8C

FRA8E

FRA8D

FRA9G

FRA9A

FRA9C