Genomes and Genes
chromosome fragile sites
Summary: Specific loci that show up during KARYOTYPING as a gap (an uncondensed stretch in closer views) on a CHROMATID arm after culturing cells under specific conditions. These sites are associated with an increase in CHROMOSOME FRAGILITY. They are classified as common or rare, and by the specific culture conditions under which they develop. Fragile site loci are named by the letters "FRA" followed by a designation for the specific chromosome, and a letter which refers to which fragile site of that chromosome (e.g. FRAXA refers to fragile site A on the X chromosome. It is a rare, folic acid-sensitive fragile site associated with FRAGILE X SYNDROME.)
- Toledo F, Coquelle A, Svetlova E, Debatisse M. Enhanced flexibility and aphidicolin-induced DNA breaks near mammalian replication origins: implications for replicon mapping and chromosome fragility. Nucleic Acids Res. 2000;28:4805-13 pubmed..As shown here, an increased sensitivity to aphidicolin was found near two mammalian DNA replication origins...
- Hewett D, Handt O, Hobson L, Mangelsdorf M, Eyre H, Baker E, et al. FRA10B structure reveals common elements in repeat expansion and chromosomal fragile site genesis. Mol Cell. 1998;1:773-81 pubmed..Somatic and intergenerational FRA10B repeat instability analogous to that found in expanded trinucleotide repeats supports dynamic mutation as a common mechanism for repeat expansion. ..
- Ozeri Galai E, Bester A, Kerem B. The complex basis underlying common fragile site instability in cancer. Trends Genet. 2012;28:295-302 pubmed publisher..Here, we review the shared and unique characteristics of CFSs, their underlying causes and their implications, particularly with respect to the development of cancer. ..
- Corbin S, Neilly M, Espinosa R, Davis E, McKeithan T, Le Beau M. Identification of unstable sequences within the common fragile site at 3p14.2: implications for the mechanism of deletions within fragile histidine triad gene/common fragile site at 3p14.2 in tumors. Cancer Res. 2002;62:3477-84 pubmed..Together, the results suggest that factors other than the DNA sequence per se are responsible for the formation of DNA breaks/gaps...
- Morelli C, Karayianni E, Magnanini C, Mungall A, Thorland E, Negrini M, et al. Cloning and characterization of the common fragile site FRA6F harboring a replicative senescence gene and frequently deleted in human tumors. Oncogene. 2002;21:7266-76 pubmed..Moreover, a gene associated to hereditary schizophrenia maps within FRA6F. Therefore, FRA6F may represent a landmark for the identification and cloning of genes involved in senescence, leukemia, cancer and schizophrenia...
- Ragland R, Glynn M, Arlt M, Glover T. Stably transfected common fragile site sequences exhibit instability at ectopic sites. Genes Chromosomes Cancer. 2008;47:860-72 pubmed publisher..These data support the hypothesis that sequences at CFSs are inherently unstable, and are a major factor in the formation of replication stress induced gaps and breaks at CFSs. ..
- Bednarek A, Laflin K, Daniel R, Liao Q, Hawkins K, Aldaz C. WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer. Cancer Res. 2000;60:2140-5 pubmed..The unique features of WWOX and its possible association with cancer processes make it an interesting target for further investigation. ..
- Howlett N, Taniguchi T, Durkin S, D Andrea A, Glover T. The Fanconi anemia pathway is required for the DNA replication stress response and for the regulation of common fragile site stability. Hum Mol Genet. 2005;14:693-701 pubmed..Following APH treatment, FANCD2-Ub co-localizes with PCNA (early) and RPA2 (late) in discrete nuclear foci. Our results demonstrate an integral role for the FA pathway in the DNA replication stress response. ..
- Pelliccia F, Bosco N, Rocchi A. Breakages at common fragile sites set boundaries of amplified regions in two leukemia cell lines K562 - Molecular characterization of FRA2H and localization of a new CFS FRA2S. Cancer Lett. 2010;299:37-44 pubmed publisher..1-q32.2), which here has been characterized molecularly; FRA2S (2q22.3-q23.3), a newly localized aphidicolin inducible CFS; and FRA2G (2q24.3-q31). ..
- Palakodeti A, Han Y, Jiang Y, Le Beau M. The role of late/slow replication of the FRA16D in common fragile site induction. Genes Chromosomes Cancer. 2004;39:71-6 pubmed
- Ludes Meyers J, Bednarek A, Popescu N, Bedford M, Aldaz C. WWOX, the common chromosomal fragile site, FRA16D, cancer gene. Cytogenet Genome Res. 2003;100:101-10 pubmed..In addition, we will discuss the possible biochemical functions of WWOX and present evidence that ectopic WWOX expression inhibits tumor growth. ..
- Denison S, Callahan G, Becker N, Phillips L, Smith D. Characterization of FRA6E and its potential role in autosomal recessive juvenile parkinsonism and ovarian cancer. Genes Chromosomes Cancer. 2003;38:40-52 pubmed..2) and FRA16D (16q23.2) in representing a large region of genomic instability and containing an extremely large gene that may play a role in the development of ovarian and many other cancers...
- Callahan G, Denison S, Phillips L, Shridhar V, Smith D. Characterization of the common fragile site FRA9E and its potential role in ovarian cancer. Oncogene. 2003;22:590-601 pubmed..This study provides evidence to suggest that instability within FRA9E may play an important role in the development of ovarian cancer and lends further support for the hypothesis that CFSs may be causally related to cancer...
- Handt O, Baker E, Dayan S, Gartler S, Woollatt E, Richards R, et al. Analysis of replication timing at the FRA10B and FRA16B fragile site loci. Chromosome Res. 2000;8:677-88 pubmed
- Schneider B, Nagel S, Kaufmann M, Winkelmann S, Bode J, Drexler H, et al. T(3;7)(q27;q32) fuses BCL6 to a non-coding region at FRA7H near miR-29. Leukemia. 2008;22:1262-6 pubmed
- Dall K, Scarpini C, Roberts I, Winder D, Stanley M, Muralidhar B, et al. Characterization of naturally occurring HPV16 integration sites isolated from cervical keratinocytes under noncompetitive conditions. Cancer Res. 2008;68:8249-59 pubmed publisher..These latter observations do not support an important role for HPV16 integration in causing insertional mutagenesis. ..
- Palumbo E, Matricardi L, Tosoni E, Bensimon A, Russo A. Replication dynamics at common fragile site FRA6E. Chromosoma. 2010;119:575-87 pubmed publisher..These results may be of general significance to address the problem of fragile site instability. ..
- Giarnieri E, Zanesi N, Bottoni A, Alderisio M, Lukic A, Vecchione A, et al. Oncosuppressor proteins of fragile sites are reduced in cervical cancer. Cancer Lett. 2010;289:40-5 pubmed publisher..Thus, WWOX may be considered as a novel important genetic marker in cervical cancer and the association between the altered expression of FHIT and WWOX may be a critical event in the progression of this neoplasia. ..
- Chan K, Palmai Pallag T, Ying S, Hickson I. Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nat Cell Biol. 2009;11:753-60 pubmed publisher..Our data have general implications concerning the contribution of fragile site loci to chromosomal instability and tumorigenesis. ..
- Ishii H, Furukawa Y. Alterations of common chromosome fragile sites in hematopoietic malignancies. Int J Hematol. 2004;79:238-42 pubmed..Thus chromosomal aberrations at common fragile sites, in addition to the well-defined hallmark leukemia chromosome translocations, are involved in clinicopathological outcomes of hematopoietic malignancies. ..
- Hsu Y, Wang Y. Human fragile site FRA16B DNA excludes nucleosomes in the presence of distamycin. J Biol Chem. 2002;277:17315-9 pubmed
- Letessier A, Millot G, Koundrioukoff S, Lachages A, Vogt N, Hansen R, et al. Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature. 2011;470:120-3 pubmed publisher..Therefore, common fragile site contribution to chromosomal rearrangements in tumours should be reassessed after mapping fragile sites in the cell type from which each tumour originates...
- Nancarrow J, Kremer E, Holman K, Eyre H, Doggett N, Le Paslier D, et al. Implications of FRA16A structure for the mechanism of chromosomal fragile site genesis. Science. 1994;264:1938-41 pubmed..The FRA16A locus in individuals who do not express the fragile site is not a site of DNA methylation (imprinting), which suggests that the methylation associated with fragile sites may be a consequence and not a cause of their genesis. ..
- Schwartz M, Zlotorynski E, Goldberg M, Ozeri E, Rahat A, le Sage C, et al. Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability. Genes Dev. 2005;19:2715-26 pubmed..These findings suggest that DSBs are formed at common fragile sites as a result of replication perturbation. The repair of these breaks by both HR and NHEJ pathways is essential for chromosomal stability at these sites. ..
- Coquelle A, Pipiras E, Toledo F, Buttin G, Debatisse M. Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons. Cell. 1997;89:215-25 pubmed..The positions of fragile sites relative to boundaries of amplicons found in human cancers support the hypothesis that fragile sites play a key role in the amplification of at least some oncogenes during tumor progression. ..
- Re A, Cora D, Puliti A, Caselle M, Sbrana I. Correlated fragile site expression allows the identification of candidate fragile genes involved in immunity and associated with carcinogenesis. BMC Bioinformatics. 2006;7:413 pubmed..Our results support the hypothesis that fragile sites serve a function; we propose that fragility is linked to a coordinated regulation of fragile genes expression. ..
- Krummel K, Denison S, Calhoun E, Phillips L, Smith D. The common fragile site FRA16D and its associated gene WWOX are highly conserved in the mouse at Fra8E1. Genes Chromosomes Cancer. 2002;34:154-67 pubmed..This evolutionary conservation suggests that the two most active CFSs share many features, and that CFSs and their associated genes may be necessary for cell survival...
- Sutherland G, Baker E. The clinical significance of fragile sites on human chromosomes. Clin Genet. 2000;58:157-61 pubmed
- Gericke G. Chromosomal fragility may be indicative of altered higher-order DNA organization as the underlying genetic diathesis in complex neurobehavioural disorders. Med Hypotheses. 1999;52:201-8 pubmed
- Sarafidou T, Kahl C, Martinez Garay I, Mangelsdorf M, Gesk S, Baker E, et al. Folate-sensitive fragile site FRA10A is due to an expansion of a CGG repeat in a novel gene, FRA10AC1, encoding a nuclear protein. Genomics. 2004;84:69-81 pubmed..Our data also suggest that in the heterozygous state FRA10A is likely a benign folate-sensitive fragile site...
- Lemoine F, Degtyareva N, Kokoska R, Petes T. Reduced levels of DNA polymerase delta induce chromosome fragile site instability in yeast. Mol Cell Biol. 2008;28:5359-68 pubmed publisher..Understanding the molecular mechanisms regulating the stability of chromosome fragile sites, therefore, has important implications in cancer biology...
- McAvoy S, Ganapathiraju S, Ducharme Smith A, Pritchett J, Kosari F, Perez D, et al. Non-random inactivation of large common fragile site genes in different cancers. Cytogenet Genome Res. 2007;118:260-9 pubmed..Instead, it appears that different cancers select for the inactivation of different large CFS genes. ..
- Tatarelli C, Linnenbach A, Mimori K, Croce C. Characterization of the human TESTIN gene localized in the FRA7G region at 7q31.2. Genomics. 2000;68:1-12 pubmed..Analysis of the TESTIN coding region in 26 tumor cell lines revealed three missense mutations. Our findings suggest that TESTIN may represent a candidate tumor suppressor gene at 7q31.2. ..
- Ruiz Herrera A, Robinson T. Chromosomal instability in Afrotheria: fragile sites, evolutionary breakpoints and phylogenetic inference from genome sequence assemblies. BMC Evol Biol. 2007;7:199 pubmed
- Zhang H, Freudenreich C. An AT-rich sequence in human common fragile site FRA16D causes fork stalling and chromosome breakage in S. cerevisiae. Mol Cell. 2007;27:367-79 pubmed..Our data suggest that the FRA16D Flex1 sequence causes increased chromosome breakage by forming secondary structures that stall replication fork progression...
- von Grotthuss M, Ashburner M, Ranz J. Fragile regions and not functional constraints predominate in shaping gene organization in the genus Drosophila. Genome Res. 2010;20:1084-96 pubmed publisher..Fragile regions rather than functional constraints have been the main determinant of the evolution of the Drosophila chromosomes...
- Murfuni I, De Santis A, Federico M, Bignami M, Pichierri P, Franchitto A. Perturbed replication induced genome wide or at common fragile sites is differently managed in the absence of WRN. Carcinogenesis. 2012;33:1655-63 pubmed publisher..Our results contribute to unveil two different mechanisms used by the cell to overcome the absence of WRN. ..
- O Keefe L, Liu Y, Perkins A, Dayan S, Saint R, Richards R. FRA16D common chromosomal fragile site oxido-reductase (FOR/WWOX) protects against the effects of ionizing radiation in Drosophila. Oncogene. 2005;24:6590-6 pubmed..This is consistent with a protective role for hWWOX where aberrant expression, as a result of breakage at the associated fragile site, could contribute directly to cancer progression. ..
- Barlow J, Faryabi R, CallÃ©n E, Wong N, Malhowski A, Chen H, et al. Identification of early replicating fragile sites that contribute to genome instability. Cell. 2013;152:620-32 pubmed publisher..Moreover, greater than 50% of recurrent amplifications/deletions in human diffuse large B cell lymphoma map to ERFSs. In summary, we have identified a source of spontaneous DNA lesions that drives instability at preferred genomic sites. ..
- Tsantoulis P, Kotsinas A, Sfikakis P, Evangelou K, Sideridou M, Levy B, et al. Oncogene-induced replication stress preferentially targets common fragile sites in preneoplastic lesions. A genome-wide study. Oncogene. 2008;27:3256-64 pubmed..CFSs were on average less flexible than nonfragile regions, contained more guanine-cytosine (GC) and Alu sequences. Importantly, regions with loss-of-heterozygosity were also less flexible and had a higher Alu percentage. ..
- Curatolo A, Limongi Z, Pelliccia F, Rocchi A. Molecular characterization of the human common fragile site FRA1H. Genes Chromosomes Cancer. 2007;46:487-93 pubmed..Among the other genes, two very large genes (USH2A, ESRRG) and two microRNA genes (MIRN194-1, MIRN215) map within the fragile region. ..
- Zhu M, Weiss R. Increased common fragile site expression, cell proliferation defects, and apoptosis following conditional inactivation of mouse Hus1 in primary cultured cells. Mol Biol Cell. 2007;18:1044-55 pubmed..In summary, we propose that Hus1 loss leads to chromosomal instability during DNA replication, triggering increased apoptosis and impaired proliferation through p53-independent mechanisms. ..
- Helmrich A, Stout Weider K, Hermann K, Schrock E, Heiden T. Common fragile sites are conserved features of human and mouse chromosomes and relate to large active genes. Genome Res. 2006;16:1222-30 pubmed..Our findings suggest that the mechanisms that provoke instability at CFSs are evolutionarily conserved. The role that large transcriptionally active genes may play in CFS expression is discussed. ..
- Hormozian F, Schmitt J, Sagulenko E, Schwab M, Savelyeva L. FRA1E common fragile site breaks map within a 370kilobase pair region and disrupt the dihydropyrimidine dehydrogenase gene (DPYD). Cancer Lett. 2007;246:82-91 pubmed
- Schwartz M, Zlotorynski E, Kerem B. The molecular basis of common and rare fragile sites. Cancer Lett. 2006;232:13-26 pubmed..Here we discuss the works performed in recent years that investigated the characteristics of fragile sites which underlie their inherent instability...
- Guler G, Uner A, Guler N, Han S, Iliopoulos D, McCue P, et al. Concordant loss of fragile gene expression early in breast cancer development. Pathol Int. 2005;55:471-8 pubmed..035). In summary, reduced Fhit and Wwox expression in in-situ breast cancer was associated, which may contribute to the high-grade DCIS-invasive tumor pathway. ..
- Finnis M, Dayan S, Hobson L, Chenevix Trench G, Friend K, Ried K, et al. Common chromosomal fragile site FRA16D mutation in cancer cells. Hum Mol Genet. 2005;14:1341-9 pubmed..Most cell lines with FRA16D homozygous deletions also have FRA3B deletions, therefore common fragile sites represent highly susceptible genome-wide targets for a distinct form of mutation. ..
- Denison S, Simper R, Greenbaum I. How common are common fragile sites in humans: interindividual variation in the distribution of aphidicolin-induced fragile sites. Cytogenet Genome Res. 2003;101:8-16 pubmed
- Sutherland G. Rare fragile sites. Cytogenet Genome Res. 2003;100:77-84 pubmed..The folate insensitive fragile sites have more complex longer repeat elements. Only two rare fragile sites (FRAXA and FRAXE) are of unequivocal clinical significance in that they are associated with intellectual disability. ..
- Le Beau M, Drabkin H, Glover T, Gemmill R, Rassool F, McKeithan T, et al. An FHIT tumor suppressor gene?. Genes Chromosomes Cancer. 1998;21:281-9 pubmed..The paradigm of FHIT emphasizes that confirming the role of a candidate tumor suppressor gene may prove difficult, particularly for those genes that are located in genetically unstable regions. ..
- Yu S, Mangelsdorf M, Hewett D, Hobson L, Baker E, Eyre H, et al. Human chromosomal fragile site FRA16B is an amplified AT-rich minisatellite repeat. Cell. 1997;88:367-74 pubmed..Therefore the mutation mechanism associated with trinucleotide repeats is also a property of minisatellite repeats (variable number tandem repeats). ..