Chromosomal fragile site

Silencing of the FMR1 Gene in Fragile X Syndrome
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 [1] when the cell is exposed to partial replication stress.[2] Based on their frequency, fragile sites are classified as "common" or "rare".[3] To date, more than 120 fragile sites have been identified in the human genome.[3][4]

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 especially 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 mental retardation.

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 [5]), and nonfolate-sensitive groups, which are induced by bromodeoxyuridine (BrdU) or distamycin A,[6] an antibiotic that preferentially binds to AT-pairs of DNA.[7] The folate-sensitive group is characterized by an expansion of CGG repeats,[8] while the nonfolate-sensitive group contains many AT-rich minisatellite repeats.[9]

Mechanisms of Instability

The CGG and AT-rich repeats characteristic of RFSs can form hairpins[10] and other non-B DNA structures that block replication forks and can result in breakage.[11][12][13] DNA polymerase has been shown to pause at CTG and CGG triplet repeat sequences, which can result in continual expansion via slippage.[14]

Common Fragile Sites

Classification

Unlike RFSs, common fragile sites (CFSs) are not the result of nucleotide repeat expansion mutations. They are a normal part of the human genome and are typically stable when not under replicative stress.[15] The majority of breakages at CFSs are induced by low doses of the antibiotic aphidocilin (APH).[16] Co-treatment with low concentrations of the topoisomerase I inhibitor, camptothecin (CPT), reduces APH-induced breakage.[17] CFS regions are highly conserved in mouse[18][19] and other species, including primates, cat, dog, pig, horse, cow, Indian mole rat, and yeast (for review, see [4]). 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.[20]

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.[4] 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.[21] Ataxia-telengiectasia and Rad3 Related (ATR) checkpoint kinase is required for maintaining stability of CFS under both stressed and normal replicating conditions.[22] Breakage is reduced after treatment with CPT (without APH), signifying that CPT also has a necessary role in stabilizing CFSs.[17]

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[23] and WWOX,[24] 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 [4] ) MicroRNA genes, which are preferentially involved in chromosomal alterations, are frequently located at fragile sites.[25] Chromosomal alterations may lead to deregulation of microRNA, which could be of diagnostic and prognostic significance for cancers.[26] Additionally, the Hepatitis B virus (HBV)[27] 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.[28][29] Fragile sites have also been implicated in a variety of syndromes (for a review, see [30]). For example, breakage at or near the FRA11b locus has been implicated in Jacobsen syndrome, which is characterized by loss of the part of the long arm of chromosome 11 accompanied by mild mental retardation.[31] The FRAXE site is associated in the development of a form of mental retardation without any distinctive phenotypic features.[30] Seckel syndrome, a genetic disease characterized by low levels of ATR, results in increased instability of chromosomes at fragile sites.[32]

Fragile Sites and Affected Genes

FRA1B

FRA1E

FRA2F

FRA3B

FRA4F

FRA5H

FRA6E

FRA7K

FRA7I

FRA10D

FRA11F

FRA13A

FRA15A

FRA16D

FRAXC

References

  1. ↑ Sutherland, GR and Hecht, F: Fragile Sites on Human Chromosomes. New York and Oxford: Oxford University Press, 280 pages (1985).
  2. ↑ Schwartz, M.; Zlotorynski, E.; Kerem, B. (2005), "The molecular basis of common and rare fragile sites", Cancer Letters 232 (1): 13–26, doi:10.1016/j.canlet.2005.07.039, PMID 16236432
  3. 1 2 Lukusa, T.; Fryns, J.P. (2008), "Human chromosome fragility", Biochimica et Biophysica Acta 1779 (1): 3–16, doi:10.1016/j.bbagrm.2007.10.005, PMID 18078840
  4. 1 2 3 4 Durkin, S.G.; Glover, T.W. (2007), "Chromosome fragile sites", Annual Review of Genetics 41: 169–192, doi:10.1146/annurev.genet.41.042007.165900, PMID 17608616
  5. ↑ Sutherland, GR; Jacky, PB; Baker, E; Manuel, A (May 1983). "Heritable fragile sites on human chromosomes. X. New folate-sensitive fragile sites: 6p23, 9p21, 9q32, and 11q23.". American Journal of Human Genetics 35 (3): 432–7. PMC 1685660. PMID 6859039.
  6. ↑ Sutherland, GR; Baker, E; Seshadri, RS (Jul 1980). "Heritable fragile sites on human chromosomes. V. A new class of fragile site requiring BrdU for expression.". American Journal of Human Genetics 32 (4): 542–8. PMC 1686118. PMID 7395866.
  7. ↑ Luck, G; Zimmer, C; Reinert, KE; Arcamone, F (Aug 1977). "Specific interactions of distamycin A and its analogs with (A-T) rich and (G-C) rich duplex regions of DNA and deoxypolynucleotides.". Nucleic Acids Research 4 (8): 2655–70. doi:10.1093/nar/4.8.2655. PMC 342599. PMID 561949.
  8. ↑ Balakumaran, BS; Freudenreich, CH; Zakian, VA (Jan 1, 2000). "CGG/CCG repeats exhibit orientation-dependent instability and orientation-independent fragility in Saccharomyces cerevisiae.". Human Molecular Genetics 9 (1): 93–100. doi:10.1093/hmg/9.1.93. PMID 10587583.
  9. ↑ Yu, S; Mangelsdorf, M; Hewett, D; Hobson, L; Baker, E; Eyre, HJ; Lapsys, N; Le Paslier, D; Doggett, NA; Sutherland, GR; Richards, RI (Feb 7, 1997). "Human chromosomal fragile site FRA16B is an amplified AT-rich minisatellite repeat.". Cell 88 (3): 367–74. doi:10.1016/S0092-8674(00)81875-9. PMID 9039263.
  10. ↑ Gacy, AM; Goellner, G; Juranić, N; Macura, S; McMurray, CT (May 19, 1995). "Trinucleotide repeats that expand in human disease form hairpin structures in vitro.". Cell 81 (4): 533–40. doi:10.1016/0092-8674(95)90074-8. PMID 7758107.
  11. ↑ Wells, RD (Feb 9, 1996). "Molecular basis of genetic instability of triplet repeats.". The Journal of Biological Chemistry 271 (6): 2875–8. doi:10.1074/jbc.271.6.2875. PMID 8621672.
  12. ↑ Zhang, Haihua; Freudenreich, Catherine H. "An AT-Rich Sequence in Human Common Fragile Site FRA16D Causes Fork Stalling and Chromosome Breakage in S. cerevisiae". Molecular Cell 27 (3): 367–379. doi:10.1016/j.molcel.2007.06.012.
  13. ↑ Aguilera, A; Gómez-González, B (Mar 2008). "Genome instability: a mechanistic view of its causes and consequences.". Nature Reviews Genetics 9 (3): 204–17. doi:10.1038/nrg2268. PMID 18227811.
  14. ↑ Ohshima, K. (10 November 1995). "Pausing of DNA Synthesis in Vitro at Specific Loci in CTG and CGG Triplet Repeats from Human Hereditary Disease Genes". Journal of Biological Chemistry 270 (45): 27014–27021. doi:10.1074/jbc.270.45.27014.
  15. ↑ Smith, DI; Huang, H; Wang, L (Jan 1998). "Common fragile sites and cancer (review).". International journal of oncology 12 (1): 187–96. doi:10.3892/ijo.12.1.187. PMID 9454904.
  16. ↑ Glover, TW; Berger, C; Coyle, J; Echo, B (1984). "DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes.". Human Genetics 67 (2): 136–42. doi:10.1007/bf00272988. PMID 6430783.
  17. 1 2 Arlt, MF; Glover, TW (Jun 4, 2010). "Inhibition of topoisomerase I prevents chromosome breakage at common fragile sites.". DNA repair 9 (6): 678–89. doi:10.1016/j.dnarep.2010.03.005. PMC 2896008. PMID 20413351.
  18. ↑ Shiraishi, T; Druck, T; Mimori, K; Flomenberg, J; Berk, L; Alder, H; Miller, W; Huebner, K; Croce, CM (May 8, 2001). "Sequence conservation at human and mouse orthologous common fragile regions, FRA3B/FHIT and Fra14A2/Fhit.". Proceedings of the National Academy of Sciences of the United States of America 98 (10): 5722–7. doi:10.1073/pnas.091095898. PMC 33280. PMID 11320209.
  19. ↑ Krummel, KA; Denison, SR; Calhoun, E; Phillips, LA; Smith, DI (Jun 2002). "The common fragile site FRA16D and its associated gene WWOX are highly conserved in the mouse at Fra8E1.". Genes, chromosomes & cancer 34 (2): 154–67. doi:10.1002/gcc.10047. PMID 11979549.
  20. ↑ Schmid, M; Ott, G; Haaf, T; Scheres, JM (1985). "Evolutionary conservation of fragile sites induced by 5-azacytidine and 5-azadeoxycytidine in man, gorilla, and chimpanzee.". Human Genetics 71 (4): 342–50. doi:10.1007/bf00388461. PMID 4077049.
  21. ↑ Zlotorynski, E; Rahat, A; Skaug, J; Ben-Porat, N; Ozeri, E; Hershberg, R; Levi, A; Scherer, SW; Margalit, H; Kerem, B (Oct 2003). "Molecular basis for expression of common and rare fragile sites.". Molecular and Cellular Biology 23 (20): 7143–51. doi:10.1128/mcb.23.20.7143-7151.2003. PMC 230307. PMID 14517285.
  22. ↑ Casper, Anne M.; Nghiem, Paul; Arlt, Martin F.; Glover, Thomas W. (1 December 2002). "ATR Regulates Fragile Site Stability". Cell 111 (6): 779–789. doi:10.1016/S0092-8674(02)01113-3.
  23. ↑ Zanesi, N; Fidanza, V; Fong, LY; Mancini, R; Druck, T; Valtieri, M; Rüdiger, T; McCue, PA; Croce, CM; Huebner, K (Aug 28, 2001). "The tumor spectrum in FHIT-deficient mice.". Proceedings of the National Academy of Sciences of the United States of America 98 (18): 10250–5. doi:10.1073/pnas.191345898. PMC 56947. PMID 11517343.
  24. ↑ Aqeilan, RI; Trapasso, F; Hussain, S; Costinean, S; Marshall, D; Pekarsky, Y; Hagan, JP; Zanesi, N; Kaou, M; Stein, GS; Lian, JB; Croce, CM (Mar 6, 2007). "Targeted deletion of Wwox reveals a tumor suppressor function.". Proceedings of the National Academy of Sciences of the United States of America 104 (10): 3949–54. doi:10.1073/pnas.0609783104. PMC 1820689. PMID 17360458.
  25. ↑ Calin, GA; Sevignani, C; Dumitru, CD; Hyslop, T; Noch, E; Yendamuri, S; Shimizu, M; Rattan, S; Bullrich, F; Negrini, M; Croce, CM (Mar 2, 2004). "Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers.". Proceedings of the National Academy of Sciences of the United States of America 101 (9): 2999–3004. doi:10.1073/pnas.0307323101. PMC 365734. PMID 14973191.
  26. ↑ Calin, GA; Croce, CM (Aug 2007). "Chromosomal rearrangements and microRNAs: a new cancer link with clinical implications.". The Journal of Clinical Investigation 117 (8): 2059–66. doi:10.1172/JCI32577. PMC 1934569. PMID 17671640.
  27. ↑ Jiang, S; Yang, Z; Li, W; Li, X; Wang, Y; Zhang, J; Xu, C; Chen, PJ; Hou, J; McCrae, MA; Chen, X; Zhuang, H; Lu, F (2012). "Re-evaluation of the carcinogenic significance of hepatitis B virus integration in hepatocarcinogenesis.". PLoS ONE 7 (9): e40363. doi:10.1371/journal.pone.0040363. PMC 3433482. PMID 22962577.
  28. ↑ Thorland, EC; Myers, SL; Gostout, BS; Smith, DI (Feb 27, 2003). "Common fragile sites are preferential targets for HPV16 integrations in cervical tumors.". Oncogene 22 (8): 1225–37. doi:10.1038/sj.onc.1206170. PMID 12606949.
  29. ↑ Wilke, CM; Hall, BK; Hoge, A; Paradee, W; Smith, DI; Glover, TW (Feb 1996). "FRA3B extends over a broad region and contains a spontaneous HPV16 integration site: direct evidence for the coincidence of viral integration sites and fragile sites.". Human Molecular Genetics 5 (2): 187–95. doi:10.1093/hmg/5.2.187. PMID 8824874.
  30. 1 2 Debacker, K; Kooy, RF (Oct 15, 2007). "Fragile sites and human disease.". Human Molecular Genetics. 16 Spec No. 2: R150–8. doi:10.1093/hmg/ddm136. PMID 17567780.
  31. ↑ Jones, C; Penny, L; Mattina, T; Yu, S; Baker, E; Voullaire, L; Langdon, WY; Sutherland, GR; Richards, RI; Tunnacliffe, A (Jul 13, 1995). "Association of a chromosome deletion syndrome with a fragile site within the proto-oncogene CBL2.". Nature 376 (6536): 145–9. doi:10.1038/376145a0. PMID 7603564.
  32. ↑ Casper, AM; Durkin, SG; Arlt, MF; Glover, TW (Oct 2004). "Chromosomal instability at common fragile sites in Seckel syndrome.". American Journal of Human Genetics 75 (4): 654–60. doi:10.1086/422701. PMC 1182052. PMID 15309689.
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