chromosome fragility

Summary

Summary: Susceptibility of chromosomes to breakage leading to translocation; CHROMOSOME INVERSION; SEQUENCE DELETION; or other CHROMOSOME BREAKAGE related aberrations.

Top Publications

  1. Fregoso M, Laine J, Aguilar Fuentes J, Mocquet V, Reynaud E, Coin F, et al. DNA repair and transcriptional deficiencies caused by mutations in the Drosophila p52 subunit of TFIIH generate developmental defects and chromosome fragility. Mol Cell Biol. 2007;27:3640-50 pubmed
    ..This study significantly extends the role of p52 in regulating XPB ATPase activity and, consequently, both its transcriptional and nucleotide excision repair functions...
  2. Glover T. Common fragile sites. Cancer Lett. 2006;232:4-12 pubmed
    ..Some aspects of this review were taken from Glover et al. (T.W. Glover, M.F. Arlt, A.M. Casper, S.G. Durkin, Mechanisms of common fragile site instability, Hum. Molec. Genet. 14 (in press). [1])...
  3. Surralles J, Jackson S, Jasin M, Kastan M, West S, Joenje H. Molecular cross-talk among chromosome fragility syndromes. Genes Dev. 2004;18:1359-70 pubmed
  4. 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...
  5. Ouyang Y, Kwon Y, An J, Eller D, Tsai S, Diaz Perez S, et al. Loss of Ubr2, an E3 ubiquitin ligase, leads to chromosome fragility and impaired homologous recombinational repair. Mutat Res. 2006;596:64-75 pubmed
    ..In contrast, Ubr2-/- cells appeared normal in an assay for non-homologous end joining. Our results therefore unveil the role of the ubiquitin ligase Ubr2 in maintaining genome integrity and in homologous recombination repair...
  6. Kim H, Narayanan V, Mieczkowski P, Petes T, Krasilnikova M, Mirkin S, et al. Chromosome fragility at GAA tracts in yeast depends on repeat orientation and requires mismatch repair. EMBO J. 2008;27:2896-906 pubmed publisher
    ..We suggest that the mechanism of GAA/TTC-induced chromosomal aberrations defined in yeast can also operate in human carriers with expanded tracts...
  7. 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...
  8. O Keefe L, Richards R. Common chromosomal fragile sites and cancer: focus on FRA16D. Cancer Lett. 2006;232:37-47 pubmed
    ..Comparative analyses of FRA3B/FHIT and FRA16D/WWOX reveal some striking similarities suggesting that these sites and their associated genes may play a part in a normal protective response of cells to environmental stress...
  9. 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...

More Information

Publications62

  1. Helmrich A, Stout Weider K, Matthaei A, Hermann K, Heiden T, Schrock E. Identification of the human/mouse syntenic common fragile site FRA7K/Fra12C1--relation of FRA7K and other human common fragile sites on chromosome 7 to evolutionary breakpoints. Int J Cancer. 2007;120:48-54 pubmed
    ..In addition, in contrast to all currently reported data, CFSs in chromosome band 7q31 do not show increased DNA helix flexibility in comparison with control regions without CFS expression...
  2. Cimprich K. Fragile sites: breaking up over a slowdown. Curr Biol. 2003;13:R231-3 pubmed
    ..Recent data suggest that these sites depend on the checkpoint kinase ATR to maintain their stability...
  3. Freudenreich C. Chromosome fragility: molecular mechanisms and cellular consequences. Front Biosci. 2007;12:4911-24 pubmed
    ..between replication and fragility, as well as identification of proteins and conditions needed to prevent chromosome fragility, have shed some light onto the reasons for breakage at common fragile sites...
  4. Jones C, Penny L, Mattina T, Yu S, Baker E, Voullaire L, et al. Association of a chromosome deletion syndrome with a fragile site within the proto-oncogene CBL2. Nature. 1995;376:145-9 pubmed
    ..These results have broad implications for the role of p(CCG)n repeat expansion in the aetiology of genetic disease involving chromosome rearrangements...
  5. 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...
  6. 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...
  7. Cantara S, Pisu M, Frau D, Caria P, Dettori T, Capezzone M, et al. Telomere abnormalities and chromosome fragility in patients affected by familial papillary thyroid cancer. J Clin Endocrinol Metab. 2012;97:E1327-31 pubmed publisher
    ..Studies carried out in our unit have demonstrated that familial papillary thyroid cancer (fPTC) patients display an imbalance, at the germinal level, in telomere-telomerase complex...
  8. Limongi M, Pelliccia F, Rocchi A. Characterization of the human common fragile site FRA2G. Genomics. 2003;81:93-7 pubmed
    ..In the fragile region, a considerable number of regions of high flexibility that may be related to the fragility are present...
  9. 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...
  10. Kumari D, Somma V, Nakamura A, Bonner W, D Ambrosio E, Usdin K. The role of DNA damage response pathways in chromosome fragility in Fragile X syndrome. Nucleic Acids Res. 2009;37:4385-92 pubmed publisher
    ..Using siRNA depletion, we show that ATR is involved in protecting the genome against FdU-induced chromosome fragility. We also show that FdU increases the number of gamma-H2AX foci seen in both normal and patient cells and ..
  11. Sutherland G, Baker E, Richards R. Fragile sites still breaking. Trends Genet. 1998;14:501-6 pubmed
    ..The mechanisms behind the changes that give rise to the cytogenetic manifestation of chromosomal fragility are now beginning to be understood...
  12. Iliopoulos D, Guler G, Han S, Druck T, Ottey M, McCorkell K, et al. Roles of FHIT and WWOX fragile genes in cancer. Cancer Lett. 2006;232:27-36 pubmed
    ..Results of our recent studies of these two fragile tumor suppressor genes were summarized at the first Fragilome meeting in Heidelberg, Feb. 2005...
  13. Castella M, Pujol R, Callen E, Ramirez M, Casado J, Talavera M, et al. Chromosome fragility in patients with Fanconi anaemia: diagnostic implications and clinical impact. J Med Genet. 2011;48:242-50 pubmed publisher
    ..b>Chromosome fragility induced by DNA interstrand crosslink (ICL)-inducing agents such as diepoxybutane (DEB) or mitomycin C (MMC) ..
  14. Ried K, Finnis M, Hobson L, Mangelsdorf M, Dayan S, Nancarrow J, et al. Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells. Hum Mol Genet. 2000;9:1651-63 pubmed
    ..FOR is therefore the principle genetic target for DNA instability at 16q23.2 and perturbation of FOR function is likely to contribute to the biological consequences of DNA instability at FRA16D in cancer cells...
  15. Gorgoulis V, Vassiliou L, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature. 2005;434:907-13 pubmed
    ..We propose that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations...
  16. Parrish J, Oostra B, Verkerk A, Richards C, Reynolds J, Spikes A, et al. Isolation of a GCC repeat showing expansion in FRAXF, a fragile site distal to FRAXA and FRAXE. Nat Genet. 1994;8:229-35 pubmed
    ..By sequence analysis, the expanded region contains a GCC repeat. PCR and sequence analysis of chromosomes from the general population indicates that the repeat is polymorphic (6 to 29 triplets), and is stable upon transmission...
  17. Jones C, Slijepcevic P, Marsh S, Baker E, Langdon W, Richards R, et al. Physical linkage of the fragile site FRA11B and a Jacobsen syndrome chromosome deletion breakpoint in 11q23.3. Hum Mol Genet. 1994;3:2123-30 pubmed
    ..The breakpoint has apparently been repaired and stabilised by the de novo addition of a telomere. These data are consistent with a role for an inherited fragile site in the aetiology of a chromosome deletion syndrome...
  18. Cianfarani S, Tedeschi B, Germani D, Prete S, Rossi P, Vernole P, et al. In vitro effects of growth hormone (GH) and insulin-like growth factor I and II (IGF-I and -II) on chromosome fragility and p53 protein expression in human lymphocytes. Eur J Clin Invest. 1998;28:41-7 pubmed
  19. Ciullo M, Debily M, Rozier L, Autiero M, Billault A, Mayau V, et al. Initiation of the breakage-fusion-bridge mechanism through common fragile site activation in human breast cancer cells: the model of PIP gene duplication from a break at FRA7I. Hum Mol Genet. 2002;11:2887-94 pubmed
    ..T47D cells thus offer a unique opportunity to observe the earliest products of the BFB cycle mechanism. Our findings constitute the first evidence that this amplification mechanism can be initiated in vivo by fragile site activation...
  20. Arlt M, Xu B, Durkin S, Casper A, Kastan M, Glover T. BRCA1 is required for common-fragile-site stability via its G2/M checkpoint function. Mol Cell Biol. 2004;24:6701-9 pubmed
    ..Furthermore, they suggest that mutations in BRCA1 or interacting proteins could lead to rearrangements at fragile sites in cancer cells...
  21. 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...
  22. Hellman A, Zlotorynski E, Scherer S, Cheung J, Vincent J, Smith D, et al. A role for common fragile site induction in amplification of human oncogenes. Cancer Cell. 2002;1:89-97 pubmed
    ..Upon replication stress, this region showed perturbed chromatin organization, predisposing it to breakage. Thus, in vivo induction of CFSs can play an important role in human oncogenesis...
  23. Casper A, Nghiem P, Arlt M, Glover T. ATR regulates fragile site stability. Cell. 2002;111:779-89 pubmed
    ..These findings have important implications for understanding both the mechanism of fragile site instability and the consequences of stalled replication in mammalian cells...
  24. 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...
  25. Peretti V, Ciotola F, Albarella S, Russo V, Di Meo G, Iannuzzi L, et al. Chromosome fragility in cattle with chronic enzootic haematuria. Mutagenesis. 2007;22:317-20 pubmed
    ..001) in animals affected by CEH (0.16+/-0.36) than that (0.09+/-0.29) found in the control. Chromosome fragility in cells of animals affected by CEH was also confirmed when applying the SCE test: statistically higher ..
  26. Lukusa T, Fryns J. Human chromosome fragility. Biochim Biophys Acta. 2008;1779:3-16 pubmed
  27. Rassool F, Le Beau M, Shen M, Neilly M, Espinosa R, Ong S, et al. Direct cloning of DNA sequences from the common fragile site region at chromosome band 3p14.2. Genomics. 1996;35:109-17 pubmed
    ..The results imply that breakage occurs at variable positions within a large region (at least on the order of 85 kb). Together, these data suggest that the structure of FRA3B differs from that of rare fragile sites...
  28. Martinez P, Thanasoula M, Muñoz P, Liao C, Tejera A, McNees C, et al. Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. Genes Dev. 2009;23:2060-75 pubmed publisher
  29. Bermejo R, Capra T, Gonzalez Huici V, Fachinetti D, Cocito A, Natoli G, et al. Genome-organizing factors Top2 and Hmo1 prevent chromosome fragility at sites of S phase transcription. Cell. 2009;138:870-84 pubmed publisher
    ..for transcription and that Hmo1 and Top2 bind in the proximity of genes transcribed in S phase suppressing chromosome fragility at the M-G1 transition...
  30. Dahm P, Olmsted A, Greenbaum I. Probability models and the applicability of statistical procedures in the identification of chromosomal fragile sites. Biometrics. 2002;58:1028-31; discussion 1032-3 pubmed
    ..2001) and emphasize the logical and statistical necessity for fragile site identifications to be based on data from single individuals...
  31. Limongi M, Pelliccia F, Rocchi A. Assignment of the human nebulin gene (NEB) to chromosome band 2q24.2 and the alpha 1 (III) collagen gene (COL3A1) to chromosome band 2q32.2 by in situ hybridization; the FRA2G common fragile site lies between the two genes in the 2q31 band. Cytogenet Cell Genet. 1997;77:259-60 pubmed
  32. Ouyang X, Wang X, Xu K, Jin D, Cheung A, Tsao S, et al. Effect of p53 on centrosome amplification in prostate cancer cells. Biochim Biophys Acta. 2001;1541:212-20 pubmed
    ..Our results indicate that p53 may play a role in the regulation of centrosome amplification and loss of p53 may be one of the mechanisms involving CIN in prostate cancer cells...
  33. Wang Y. Chromatin structure of human chromosomal fragile sites. Cancer Lett. 2006;232:70-8 pubmed
    ..This fragile site-associated chromatin structure might play an active role in DNA metabolic processes such as replication, transcription, repair and recombination, which are closely linked to the instability of fragile sites...
  34. Talmoudi F, Kilani O, Ayed W, Ben Halim N, Mellouli F, Torjmane L, et al. Differentiation of Fanconi anemia and aplastic anemia using mitomycin C test in Tunisia. C R Biol. 2013;336:29-33 pubmed publisher
    ..Twenty-six siblings of FA patients were also evaluated and five of them (19.23%) were diagnosed as FA. From this study, a standard protocol for diagnosis of FA was developed. It is routinely used as a diagnostic test of FA in Tunisia...
  35. Mrasek K, Schoder C, Teichmann A, Behr K, Franze B, Wilhelm K, et al. Global screening and extended nomenclature for 230 aphidicolin-inducible fragile sites, including 61 yet unreported ones. Int J Oncol. 2010;36:929-40 pubmed
    ..To handle FS better in future, an extension of the already existing alphabetical nomenclature for FS on single chromosomes is suggested...
  36. Sutherland G, Baker E, Callen D. A BrdU-enhanceable fragile site or viral modification site at 11q23.1 in lymphoblastoid cultures. Cytogenet Cell Genet. 1988;47:201-3 pubmed
    ..1. The low spontaneous expression of this lesion is greatly enhanced by BrdU and n-butyric acid. The lesion was expressed homozygously in all 16 cell lines examined. It is suggested that the lesion is a viral chromosome modification site...
  37. Dabrowski P, Szyfter K. [Analysis of chromosome instability as a genetic risk factor of laryngeal cancer]. Otolaryngol Pol. 2001;55:13-8 pubmed
  38. Brodeur G, Seeger R. Gene amplification in human neuroblastomas: basic mechanisms and clinical implications. Cancer Genet Cytogenet. 1986;19:101-11 pubmed
    ..001). Thus, amplification of the N-myc oncogene is a new intrastage prognostic factor, and N-myc amplification appears to play an important role in determining disease progression...
  39. Tommerup N, Leffers H. Assignment of human KH-box-containing genes by in situ hybridization: HNRNPK maps to 9q21.32-q21.33, PCBP1 to 2p12-p13, and PCBP2 to 12q13.12-q13.13, distal to FRA12A. Genomics. 1996;32:297-8 pubmed
  40. Glover T, Hoge A, Miller D, Ascara Wilke J, Adam A, Dagenais S, et al. The murine Fhit gene is highly similar to its human orthologue and maps to a common fragile site region. Cancer Res. 1998;58:3409-14 pubmed
    ..Thus, the physical relationship of Fhit to a common fragile site is similar to that observed with the orthologous human FHIT gene and FRA3B...
  41. Stenerlow B, Karlsson K, Cooper B, Rydberg B. Measurement of prompt DNA double-strand breaks in mammalian cells without including heat-labile sites: results for cells deficient in nonhomologous end joining. Radiat Res. 2003;159:502-10 pubmed
    ..A study of cells deficient in nonhomologous end joining reveals that the residual fast repair response typically seen in such cells is solely due to repair at heat-labile sites and is not due to repair of prompt DSBs...
  42. Haruki N, Harano T, Masuda A, Kiyono T, Tatematsu Y, Shimizu S, et al. Persistent increase in chromosome instability in lung cancer: possible indirect involvement of p53 inactivation. Am J Pathol. 2001;159:1345-52 pubmed
  43. Popovici C, Basset C, Bertucci F, Orsetti B, Adélaïde J, Mozziconacci M, et al. Reciprocal translocations in breast tumor cell lines: cloning of a t(3;20) that targets the FHIT gene. Genes Chromosomes Cancer. 2002;35:204-18 pubmed
    ..Additional experiments using comparative genomic hybridization provided further information on the genomic context in which the t(3;20)(p14;p11) reciprocal translocation was found...
  44. Kenneson A, Warren S. The female and the fragile X reviewed. Semin Reprod Med. 2001;19:159-65 pubmed
  45. Tuteja N, Tuteja R. Unraveling DNA repair in human: molecular mechanisms and consequences of repair defect. Crit Rev Biochem Mol Biol. 2001;36:261-90 pubmed
    ..This review describes the biochemistry of various repair processes and summarizes the clinical features and molecular mechanisms underlying these disorders...
  46. Ge X, Tanaka K, Mansyur A, Tazawa H, Iwato K, Kyo T, et al. Possible prediction of myeloid and lymphoid crises in chronic myelocytic leukemia at onset by determining the methylation status of the major breakpoint cluster region. Cancer Genet Cytogenet. 2001;126:102-10 pubmed
  47. Lavanchy L, Munier F, Cousin P, Gaide A, Thonney F, Schorderet D. Molecular characterization of the deletion in retinoblastoma patients with 13q14 cytogenetic anomalies. Ophthalmic Genet. 2001;22:1-10 pubmed
    ..The cytogenetic abnormalities around 13q14 correlate with the molecular deletions that were observed in this study. Associated malformations cannot be easily predicted from the size of the deletions...
  48. Yu A, Fan H, Liao D, Bailey A, Weiner A. Activation of p53 or loss of the Cockayne syndrome group B repair protein causes metaphase fragility of human U1, U2, and 5S genes. Mol Cell. 2000;5:801-10 pubmed
    ..Activation of p53 would inhibit CSB, stalling transcription complexes and locally blocking chromatin condensation. Impaired transcription elongation may also explain the diverse clinical features of Cockayne syndrome...
  49. Huebner K, Garrison P, Barnes L, Croce C. The role of the FHIT/FRA3B locus in cancer. Annu Rev Genet. 1998;32:7-31 pubmed
    ..FRA3B thus fulfills the prophecy that fragile site alterations contribute to the neoplastic process through inactivation of a tumor suppressor gene...
  50. 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...
  51. Smith M, Borsatto B. Down's syndrome, ageing and fragile sites. Mech Ageing Dev. 1998;101:167-73 pubmed
    ..The results showed that the fragile site 2q11 was associated with the DS condition and fragile sites 5q31, 6p21 and 9q12 with ageing in DS subjects. Fragility in 6p21 has also been associated with Alzheimer's disease patients...
  52. Devon R, Porteous D. Physical mapping of a glutamate receptor gene in relation to a balanced translocation associated with schizophrenia in a large Scottish family. Psychiatr Genet. 1997;7:165-9 pubmed
    ..However, a long range position effect of the translocation on this gene, or co-segregation of the translocation with a mutant allele of mGluR5a cannot be ruled out...
  53. Ankathil R, Kusumakumary P, Priyakumary T, Krishnan Nair M. Expression of folate sensitive and aphidicolin induced chromosomal fragile sites in familial neuroblastoma. J Exp Clin Cancer Res. 2002;21:383-8 pubmed
    ..A larger number of subjects have to be studied to prove whether altered fragile site expression may be a cytogenetic evidence for an individual or familial cancer predisposing genetic constitution...