A chromosomal fragile site is a specific heritable point on a

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

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 In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...

. 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 Bis(5'-adenosyl)-triphosphatase also known as fragile histidine triad protein (FHIT) is an enzyme that in humans is encoded by the ''FHIT'' gene. Function FHIT is also known as human accelerated region 10. It may, therefore, have played a key ...

'' gene) and FRA16D (harboring the ''

WWOX WW domain-containing oxidoreductase is an enzyme that in humans is encoded by the ''WWOX'' gene. Function WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular func ...

'' 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 in the FMR1 gene, which is associated with the

fragile X syndrome Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may ...

, 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 Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...

-sensitive groups (for examples, see ), and nonfolate-sensitive groups, which are induced by

bromodeoxyuridine Bromodeoxyuridine (5-bromo-2'-deoxyuridine, BrdU, BUdR, BrdUrd, broxuridine) is a synthetic nucleoside analogue with a chemical structure similar to thymidine. BrdU is commonly used to study cell proliferation in living tissues and has been stud ...

(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 A minisatellite is a tract of repetitive DNA in which certain DNA motifs (ranging in length from 10–60 base pairs) are typically repeated 5-50 times. Minisatellites occur at more than 1,000 locations in the human genome and they are notable for ...

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 fork In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...

s and can result in breakage.

DNA polymerase A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...

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 aphidicolin . Co-treatment with low concentrations of the

topoisomerase I DNA topoisomerases (or topoisomerases) are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. Topological issues i ...

inhibitor,

camptothecin Camptothecin (CPT) is a topoisomerase inhibitor. It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of ''Camptotheca acuminata'' (Campt ...

(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 Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic informa ...

and not. The FRAXA site is perhaps most famous for its role in

Fragile X syndrome Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may ...

, but fragile sites are clinically implicated in many other important diseases, such as

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. FRA3B and FRA16D lie within the large tumor-suppressor genes,

and

, 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 MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...

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 ''Hepatitis B virus'' (HBV) is a partially double-stranded DNA virus, a species of the genus ''Orthohepadnavirus'' and a member of the ''Hepadnaviridae'' family of viruses. This virus causes the disease hepatitis B. Disease Despite there bein ...

(HBV) and HPV-16 virus, the strain of

human papilloma virus Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and res ...

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 A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

. 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 Jacobsen syndrome is a rare chromosomal disorder resulting from deletion of genes from chromosome 11 that includes band 11q24.1. It is a congenital disorder. Since the deletion takes place on the q arm of chromosome 11, it is also called 11q te ...

, which is characterized by loss of part of the long arm of

chromosome 11 Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...

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 Seckel syndrome, or microcephalic primordial dwarfism (also known as bird-headed dwarfism, Harper's syndrome, Virchow–Seckel dwarfism and bird-headed dwarf of Seckel) is an extremely rare congenital nanosomic disorder. Inheritance is autosomal r ...

, a genetic disease characterized by low levels of ATR, results in increased instability of chromosomes at fragile sites.

Fragile sites and affected genes

* FRA1A * FRA1B (

DAB1 The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway that c ...

gene) * FRA1C * FRA1D * FRA1E (

DPYD In enzymology, a dihydropyrimidine dehydrogenase (NADP+) () is an enzyme that catalyzes the chemical reaction :5,6-dihydrouracil + NADP+ \rightleftharpoons uracil + NADPH + H+ Thus, the two substrates of this enzyme are 5,6-dihydrouracil a ...

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 (

gene) * FRA3C ( NAALADL2 gene) * FRA3D * FRA4A * FRA4B * FRA4C * FRA4D * FRA4E * FRA4F (

GRID2 Glutamate receptor, ionotropic, delta 2, also known as GluD2, GluRδ2, or δ2, is a protein that in humans is encoded by the ''GRID2'' gene. This protein together with GRID1, GluD1 belongs to the delta receptor subtype of ionotropic glutamate rec ...

gene) * FRA5A * FRA5B * FRA5C * FRA5D * FRA5E * FRA5F * FRA5G * FRA5H (

PDE4D cAMP-specific 3',5'-cyclic phosphodiesterase 4D is an enzyme that in humans is encoded by the ''PDE4D'' gene. Function The PDE4D gene is complex and has at least 9 different isoforms that encode functional proteins. These proteins degrade the s ...

gene) * FRA6A * FRA6B * FRA6C * FRA6D * FRA6E (

PARK2 Parkin is a 465-amino acid residue E3 ubiquitin ligase, a protein that in humans and mice is encoded by the ''PARK2'' gene. Parkin plays a critical role in ubiquitination – the process whereby molecules are covalently labelled with ubiquitin (Ub ...

gene) * FRA6F * FRA6G * FRA6H * FRA7A * FRA7B * FRA7C * FRA7D * FRA7E * FRA7F * FRA7G * FRA7H * FRA7I (

CNTNAP2 Contactin-associated protein-like 2 is a protein that in humans is encoded by the ''CNTNAP2'' gene. Since the most recent reference human genome GRCh38, CNTNAP2 is the longest gene in the human genome This gene encodes a member of the neurexin fa ...

gene) * FRA7J * FRA7K (

IMMP2L Inner mitochondrial membrane peptidase subunit 2 (IMMP2L) is an enzyme that in humans is encoded by the ''IMMP2L'' gene on chromosome 7. This protein catalyzes the removal of transit peptides required for the targeting of proteins from the mitoch ...

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 Disks large homolog 2 (DLG2) also known as channel-associated protein of synapse-110 (chapsyn-110) or postsynaptic density protein 93 (PSD-93) is a protein that in humans is encoded by the ''DLG2'' gene. Function Chapsyn-110/PSD-93 a member of ...

gene) * FRA11G * FRA11H * FRA11I * FRA12A * FRA12B * FRA12C * FRA12D * FRA12E * FRA13A ( NBEA gene) * FRA13B * FRA13C * FRA13D * FRA13E * FRA14B (GPHN gene) * FRA14C * FRA15A (

RORA Rora may refer to: * Rora (name) *Rora, a village administered by the city of Sighișoara, Mureș County, Romania *Rora, Aberdeenshire, a rural settlement in Aberdeenshire, Scotland *Rora, a diminutive of the Russian feminine first name Avrora (a fo ...

gene) * FRA16A * FRA16B * FRA16C * FRA16D (

gene) * FRA16E * FRA17A * FRA17B * FRA18A * FRA18B * FRA18C * FRA19A * FRA19B * FRA20A * FRA20B * FRA22A * FRA22B * FRAXB * FRAXC ( IL1RAPL1/DMD gene) * FRAXD * FRAXA * FRAXE * FRAXF

References

{{DEFAULTSORT:Fragile Sites Cytogenetics