Features of trinucleotide repeat instability in vivo

Cell Research

Volumn 18, Issue 1, 2008, Pages 198-213

  Kovtun, Irina V ^a   McMurray, Cynthia T ^a  

^a MAYO GRADUATE SCHOOL   (United States)

Author keywords

Base excision repair; Break repair; Huntington's disease; Microsatellite instability; Myotonic dystrophy; OGG1; Trinucleotide repeats

Indexed keywords

ANIMAL; BIOLOGICAL MODEL; CHROMATIN; CONFORMATION; GENE FREQUENCY; GENETIC DISORDER; GENETICS; HUMAN; INCIDENCE; MICROSATELLITE INSTABILITY; MOLECULAR GENETICS; NUCLEOTIDE SEQUENCE; PHYSIOLOGY; REGULATORY SEQUENCE; REVIEW; TRINUCLEOTIDE REPEAT;

ANIMALS; BASE SEQUENCE; CHROMATIN; GENE FREQUENCY; GENETIC DISEASES, INBORN; HUMANS; INCIDENCE; MICROSATELLITE INSTABILITY; MODELS, BIOLOGICAL; MOLECULAR SEQUENCE DATA; NUCLEIC ACID CONFORMATION; REGULATORY ELEMENTS, TRANSCRIPTIONAL; TRINUCLEOTIDE REPEATS;

BACTERIA (MICROORGANISMS); MAMMALIA; MUS;

EID: 38049100631     PISSN: 10010602     EISSN: 17487838     Source Type: Journal    
DOI: 10.1038/cr.2008.5     Document Type: Review

References (174)

1. Tautz D. Hypervariability of simple sequences as a general source for polymorphic DNA markers. Nucleic Acids Res 1989; 17:6463-6471.
2. Mrázek J, Guo X, Shah A. Simple sequence repeats in prokaryotic genomes. Proc Natl Acad Sci USA 2007; 104:8472-8477.
3. Toth G, Gaspari Z, Jurka J. Microsatellites in different eukaryotic genomes: survey and analysis. Genome Res 2000; 10:967-981.
4. Jurka J, Pethiyagoda C. Simple repetitive DNA sequences from primates: compilation and analysis. J Mol Evol 1995; 40:120-126.
5. Gáspári Z, Ortutayb C, Tóth G. Divergent microsatellite evolution in the human and chimpanzee lineages. FEBS Lett 2007; 581:2523-2526.
6. Beckman JS, Weber JL. Survey of human and rat microsatellites. Genomics 1992; 12:627-631.
7. Djian P, Hancock JM, Chana HS. Codon repeats in genes associated with human diseases: fewer repeats in the genes of nonhuman primates and nucleotide substitutions concentrated at the sites of reiteration. Proc Natl Acad Sci USA 1996; 93:417-421.
8. Durkin SG, Glover TW. Chromosome Fragile Sites. Annu Rev Genet 2007 Jul 3; doi:10.1146/annurev.genet.41.042007.165900.
9. Yant SR, Wu X, Huang Y, Garrison B, Burgess SM, Kay MA. High-resolution genome-wide mapping of transposon integration in mammals. Mol Cell Biol 2005; 6:2085-2094.
10. Jeffreys AJ, Holloway JK, Kauppi L, et al. Meiotic recombination hot spots and human DNA diversity. Philos Trans R Soc LondB Biol Sci 2004; 359:141-152.
11. Gatchel JR, Zoghbi HY. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Gene 2005; 6:743-755.
12. Mirkin SM. Expandable DNA repeats and human disease. Nature 2007 447:932-940.
13. Kwak EL, Chung DC. Hereditary colorectal cancer syndromes: an overview. Clin Colorectal Cancer 2007; 6:340-344.
14. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003; 348:919-932.
15. Peinado MA, Malkhosyan S, Velazquez A, Perucho M. Isolation and characterization of allelic loss and gains in colorectal tumors by arbitrarily primed polymerase chain reaction. Proc Natl Acad Sci USA 1992; 89: 10065-10069.
16. Liu B, Parsons R, Papadopoulos N, et al. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med 1996; 2:169-174.
17. Forgacs E, Wren JD, Kamibayashi C, et al. Searching for microsatellite mutations in coding regions in lung, breast, ovarian and colorectal cancers. Oncogene 2001; 20:1005-1009.
18. Chan TL, Yuen ST, Kong CK, et al. Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat Genet 2006; 38:1178-1183.
19. Miyaki M, Konishi M, Tanaka K, et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 1997; 17:271-272.
20. Hitchins M, Williams R, Cheong K, et al. MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Gastroenterology 2005; 129:1392-1399.
21. Suchy J, Kurzawski G, Jakubowska A, Lubinski J. Ovarian cancer of endometrioid type as part of the Msh6 gene mutation phenotype. J Hum Genet 2001; 47:529-531.
22. Wijnen J, de Leeuw W, Vasen H, et al. Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet 1999; 23:142-144.
23. Chiaravalli AM, Furlan D, Facco C, et al. Immunohistochemical pattern of hMsh2/ hMlh1 in familial and sporadic colorectal, gastric, endometrial and ovarian carcinomas with instability in microsatellite sequences. Vichows Archiv 2001; 438:39-48.
24. Castiglia D, Pagani E, Alvino E, et al. Biallelic somatic inactivation of the mismatch repair gene MLH1 in a primary skin melanoma. Genes Chromosomes Cancer 2003; 37:165-175.
25. Krüger S, Kinzel M, Walldorf C, et al. Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1. Eur J Hum genet 2007 Sep 12; doi:10.1038/sj.ejhg.5201923.
26. Suter CM, Martin DI, Ward RL. Germline epimutation of MLH1 in individuals with multiple cancers. Nat Genet 2004; 36:497-501.
27. Bacani J, Zwingerman R, Di Nicola N, et al. Tumor microsatellite instability in early onset gastric cancer. J Mol Diagn 2005; 7:465-477.
28. Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 1998; 95:6870-6875.
29. Strathdee G, MacKean MJ, Illand M, Brown R. A role for methylation of the hMlh1 promoter in loss of hMlh1 expression and drug resistance. Oncogene 1999; 18:2335-2341.
30. Kane MF, Loda M, Gaida GM, et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 1997; 57:808-811.
31. Kashi Y, King DG. Simple sequence repeats as advantageous mutators in evolution. Trends Genet 2006; 22:253-259.
32. Loeb LA. A mutator phenotype in cancer. Cancer Res 2001; 61:3230-3239.
33. Beckman RA, Loeb LA. Genetic instability in cancer: theory and experiment. Semin Cancer Biol 2005; 15:423-435.
34. Sammalkorpi H, Alhopuro P, Lehtonen R, et al. Background mutation frequency in microsatellite-unstable colorectal cancer. Cancer Res 2007; 67:5691-5698.
35. Sia EA, Kokoska RJ, Dominska M, Greenwell P, Petes TD. Microsatellite instability in yeast: dependence on repeat unit size and DNA mismatch repair genes. Mol Cell Biol 1997; 17:2851-2858.
36. Viguera E, Canceill D, Ehrlich SD. Replication slippage involves DNA polymerase pausing and dissociation. EMBO J 2001; 20:2587-2795.
37. Harr B, Todorova J, Schlotterer C. Mismatch repair-driven mutational bias in D. melanogaster. Mol Cell 2002; 10:199-205.
38. Goellner GM, Tester D, Thibodeau S, et al. Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer. Am J Hum Genet 1997; 60:879-890.
39. Manley K, Shirley, TL, Flaherty L, Messer A. MSH2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat Genet 1999; 23:471-473.
40. van den Broek WJ, Nelen M, Wansink DG, et al. Somatic expansion behavior of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch-repair proteins. Hum Mol Genet 2002; 11:191-199.
41. Wheeler V, Lebel LA, Vrbanac V, Teed A, te Riele H, MacDonald ME. Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum. Hum Mol Genet 2003; 12:273-281.
42. Savouret C, Brisson E, Essers J, et al. CTG repeat instability and size variation timing in DNA repair-deficient mice. EMBO J 2003; 22: 2264-2273.
43. Owen BA, Badger II JD, Yang Z, et al. (CAG)(n)-hairpin DNA binds to Msh2-Msh3 and changes properties of mismatch recognition. Nat Structural Mol Biol 2005; 12:663-670.
44. Cummings CJ, Zoghbi HY. Trinucleotide repeats: mechanisms and pathophysiology. Ann Rev Genom Hum Genet 2000; 1:281-328.
45. Duyao M, Ambrose C, Myers R, et al. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nat Genet 1993; 4:387-392.
46. Zuhlke C, Riess O, Bockel, B, Lange H, Thies U. Mitotic stability and meiotic variability of the (CAG)n repeat in the Huntington disease gene. Hum. Mol. Genet. 1993; 2:2063-2067.
47. Norremolle A, Sorensen SA, Fenger K, Hasholt L. Correlation between magnitude of CAG repeat length alterations and length of the paternal repeat in paternally inherited Huntington's disease Clin. Genet 1995; 47: 113-119.
48. Chong SS, Almqvist E, Telenius H, et al. Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analysis. Hum Mol Genet 1997; 6:301-309.
49. Goldberg P, McMurray CT, Zeisler J, et al. Increased instability of intermediate alleles in families with sporadic Huntington's disease compared to similar sized intermediate alleles in the general population. Hum Mol Genet 1995; 4:1911-1918.
50. Leeflang EP, Tavare S, Marjoram P, et al. Analysis of germline mutation spectra at the Huntington's disease locus supports a mitotic mutation mechanism. Hum Mol Genet 1999; 8:173-183.
51. Leeflang EP, Zhang L, Tavare S, et al. Single spermanalysis of the trinucleotide repeats in the Huntington's disease gene: quantification on the mutation frequency spectrum. Hum Mol Genet 1995; 4:1519-1526.
52. Telenius H, Kremer B, Goldberg YP, et al. Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm. Nat Genet 1994; 6:409-414.
53. Kennedy L, Evans E, Chen CM, et al. Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum Mol Genet 2003; 12:3359-3367.
54. Kennedy L, Shelbourne PF. Dramatic mutation instability in HD mouse striatum: does polyglutamine load contribute to cellspecific vulnerability in Huntington's disease? Hum Mol Genet 2000; 9:2539-2544.
55. Wohrle D, Hennig I, Vogel W, Steinbach P. Mitotic stability of fragile X mutations in differentiated cells indicates early postconceptional trinucleotide repeat expansion. Nat Genet 1993; 4:140-142.
56. Mangiarini L, Sathasivam K, Mahal A, Mott R, Seller M, Bates GP. Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation. Nat Genet 1997; 15:197-200.
57. Wong LJ, Ashizawa T, Monckton DG, Caskey CT, Richards CS. Somatic heterogeneity of the CTG repeat in myotonic dystrophy is age and size dependent. Am J Hum Genet 1995; 56:114-122.
58. Jansen G, Willems P, Coerwinkel M, et al. Gonosomal mosaicism in myotonic dystrophy patients: involvement of mitotic events in (CTG)n repeat variation and selection against extreme expansion in sperm. Am J Hum Genet 1994; 54:575-585.
59. Zhang L, Leeflang EP, Yu J, Arnheim N. Studying human mutations by sperm typing: instability of CAG trinucleotide repeats in the human androgen receptor gene. Nat Genet 1994; 7:531-535.
60. Chen X, Mariappan SVS, Catasti P, et al. Hairpins are formed by the single DNA strands of the fragile X triplet repeats: structure and biological implications. Proc Natl Acad Sci USA 1995; 92:5199-5203.
61. Gacy AM, Goellner G, Juranic N, Macura S, McMurray CT. Trinucleotide repeats that expand in human disease form hairpin structures in vitro. Cell 1995; 81:533-540.
62. McMurray CT. DNA secondary structure: a common and causative factor for expansion in human disease. Proc Natl Acad Sci USA 1999; 96: 1823-1825.
63. 15. Nucleic Acids Res 1995; 23:1050-1059.
64. Gacy AM, McMurray CT. Influence of hairpins on template reannealing at trinucleotide repeat duplexes: a model for slipped DNA. Biochemistry 1998; 37:9426-9434.
65. Sinden RR, Pytlos-Sinden MJ, Potaman VN. Slipped strand DNA structures. Front Biosci 2007; 12:4788-4799.
66. neurological diseases. Amsterdam: Elsevier/Academic Press 2006; 679-690.
67. Kang S, Jaworski A, Ohshima K, Wells RD. Expansion and deletion of CTG repeats from human disease genes are determined by the direction of replication in E. coli. Nat Genet 1995; 10:213-218.
68. Freudenreich CH, Stavenhagen JB, Zakian VA. Stability of a CTG/CAG trinucleotide repeat in yeast is dependent on its orientation in the genome. Mol Cell Biol 1997; 17:2090-2098.
69. Miret JJ, Pessoabrandao L, Lahue RS. Orientation-dependent and sequence specific expansions of CTG/CAG trinucleotide repeats in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 1998; 95:12438-12443.
70. Schweitzer JK, Livingston DM. The effect of DNA replication mutations on CAG tract stability in yeast. Genetics 1999; 152:953-963.
71. Hashem VI, Rosche WA, Sinden RR. Genetic assays for measuring rates of (CAG).(CTG) repeat instability in Escherichia coli. Mutat Res 2002; 502:25-37.
72. Kroutil LC, Kunkel TA. Deletion errors generated during replication of CAG repeats. Nucleic Acids Res 1999; 27:3481-3486.
73. Zahra R, Blackwood JK, Sales J, Leach DR. Proofreading and secondary structure processing determine the orientation dependence of CAG • CTG trinucleotide repeat instability in Escherichia coli. Genetics 2007; 176:27-41.
74. Shimizu M, Gellibolian R, Oostra BA, Wells RD. Cloning, characterization and properties of plasmids containing CGG triplet repeats from the FMR-1 gem. J Mol Biol 1996; 258:614-626.
75. Balakumaran BS, Freudenreich CH, Zakian VA. CGG/CCG repeats exhibit orientation-dependent instability and orientationindependent fragility in Saccharomyces cerevisiae. Hum Mol Genet 2000; 9:93-100.
76. Hirst MC, White PJ. Cloned human FMR1 trinucleotide repeats exhibit a length- and orientation-dependent instability suggestive of in vivo lagging strand secondary structure. Nucleic Acids Res 1998; 26:2353-2358.
77. Pollard LM, Sharma R, Gomez M, et al. Replication-mediated instability of the GAA triplet repeat mutation in Friedreich ataxia. Nucleic Acids Res 2004; 3:5962-5971.
78. Heidenfelder BL, Makhov AM, Topal MD. Hairpin formation in Friedreich's ataxia triplet repeat expansion. J Biol Chem 2003; 278:2425-2431.
79. Rosche WA, Jaworski A, Kang S, et al. Single-stranded DNA-binding protein enhances the stability of CTG triplet repeats in Escherichia coli. J Bacteriol 1996; 178:5042-5044.
80. Hartenstine MJ, Goodman MF, Petruska J. Base stacking and even/odd behavior of hairpin loops in DNA triplet repeat slip-page and expansion with DNA polymerase. J Biol Chem 2000; 275:18382-18390.
81. Gacy AM, McMurray CT. Influence of hairpins on template reannealing at trinucleotide repeat duplexes: a model for slipped DNA. Biochemistry 1998; 37:9426-9434.
82. Panigrahi GB, Lau R, Montgomery SE, Leonard MR, Pearson CE. Slipped (CTG) • (CAG) repeats can be correctly repaired, escape repair or undergo error-prone repair. Nat Struct Mol Biol 2005; 12:654-662.
83. Gordenin DA, Kunkel TA, Resnick MA. Repeat expansion - all in a flap? Nat Genet 1997; 16:116-118.
84. Iyer RR, Wells RD.Expansion and deletion of triplet repeat sequences in Escherichia coli occur on the leading strand of DNA replication. J Biol Chem 1999; 274:3865-3877.
85. Schweitzer JK, Livingston DM. Expansions of CAG repeat tracts are frequent in a yeast mutant defective in Okazaki fragment maturation. Hum Mol Genet 1998; 7:69-74.
86. Schumacher S, Pinet I, Bichara M. Modulation of transcription reveals a new mechanism of triplet repeat instability in Escherichia coli. JMoI Biol 2001; 307:39-49.
87. Bowater RP, Jaworski A, Larson JE, Parniewski P, Wells RD.Transcription increases the deletion frequency of long CTG. CAG triplet repeats from plasmids in Escherichia coli. Nucleic Acids Res 1997; 25:2861-2868.
88. Lin Y, Dion V, Wilson JH. Transcription promotes contraction of CAG repeat tracts in human cells. Nat Struct Mol Biol 2006; 13:179-180.
89. Kang S, Ohshima K, Shimizu M, Amirhaeri S, Wells RD. Pausing of DNA synthesis in vitro at specific loci in CTG and CGG triplet repeats from human hereditary disease genes. J Biol Chem 1995; 270:27014-27021.
90. Ohshima K, Wells RD. Hairpin formation during DNA synthesis primer realignment in vitro in triplet repeat sequences from human hereditary disease genes. J Biol Chem. 1997; 272:16798-16806.
91. Hartenstine MJ, Goodman MF, Petruska J. Weak strand displacement activity enables human DNA polymerase beta to expand CAG/CTG triplet repeats at strand breaks. J Biol Chem 2002; 277:41379-41389.
92. Petruska J, Hartenstine MJ, Goodman MF. Analysis of strand slippage in DNA polymerase expansions of CAG/CTG triplet repeats associated with neurodegenerative disease. J Biol Chem 1998; 273:5204-5210.
93. Heidenfelder BL, Topai MD. Effects of sequence on repeat expansion during DNA replication. Nucleic Acids Res 2003; 31:7159-7164.
94. Samadashwily GM, Raca G, Mirkin SM. Trinucleotide repeats affect DNA replication in vivo. Nature Genet 1997; 17:298-304.
95. Pelletier R, Krasilnikova MM, Samadashwily GM, Lahue R, Mirkin SM. Replication and expansion of trinucleotide repeats in yeast. Mol Cell Biol 2003; 23:1349-1357.
96. Krasilnikova MM, Mirkin SM. Replication stalling at Friedreich's ataxia (GAA)n repeats in vivo. Mol Cell Biol 2004; 24:2286-2295.
97. Fukuda H, Katahira M, Tsuchiya N, et al. Unfolding of quadruplex structure in the G-rich strand of the minisatellite repeat by the binding protein UP1. Proc Natl Acad Sci USA 2002; 99:12685-12690.
98. Fukuda H, Katahira M, Tanaka E, et al. Unfolding of higher DNA structures formed by the d(CGG) triplet repeat by UP1 protein. Genes Cells 2005; 10:953-962.
99. Fry M, Loeb LA. Human Werner syndrome DNA helicase unwinds tetrahelical structures of the fragile X syndrome repeat sequence d(CGG)n. J Biol Chem 1999; 274:12797-802.
100. Kamath-Loeb AS, Loeb LA, Johansson E, Burgers PM, Fry M. Interactions between the Werner syndrome helicase and DNA polymerase delta specifically facilitate copying of tetraplex and hairpin structures of the d(CGG)n trinucleotide repeat sequence. J Biol Chem 2001; 276:16439-16446.
101. Wang W, Bambara RA. Human Bloom protein stimulates flap endonuclease 1 activity by resolving DNA secondary structure. J Biol Chem 2005; 280:5391-5399.
102. Bhattacharyya S, Lahue RS. Srs2 helicase of Saccharomyces cerevisiae selectively unwinds triplet repeat DNA. J Biol Chem 2005; 280:33311-33317.
103. Kim SH, Rytlos MJ, Sinden RR. Replication restart: a pathway for (CTG).(CAG) repeat deletion in Escherichia coli. Mutat Res 2006; 595:5-22.
104. Hashem VI, Rosche WA, Sinden RR. Genetic recombination destabilizes (CTG)n.(CAG)n repeats in E. coli. Mutat Res 2004; 554:95-109.
105. Freudenreich, CH, Kantro, SM, Zakian VA. Expansion and length-dependent fragility of CTG repeats in yeast. Science 1998; 270:853-856.
106. Paques F, Leung, WY, Haber JE. Expansions and contractions in a tandem repeat induced by double-strand break repair. Mol Cell Biol 1998; 18:2045-2054.
107. Richard GF, Dujon B, Haber JE. Double-strand break repair can lead to high frequencies of deletions within short CAG/CTG trinucleotide repeats. Mol Gen Genet 1999; 261:871-882.
108. Jankowski C, Nasar F, Nag DK. Meiotic instability of CAG repeat tracts occurs by double-strand break repair in yeast. Proc Natl Acad Sci USA 2000; 97:2134-2139.
109. Richard GF, Goellner GM, McMurray CT, Haber JE. Recombination-induced CAG trinucleotide repeat expansions in yeast involve the MRE11/RAD50/XRS2 complex. EMBO J 2000; 19:2381-2390.
110. Jakupciak JP, Wells RD. Gene conversion (recombination) mediates expansions of CTG'CAG repeats. J Biol Chem 2000; 275:40003-40013.
111. Parniewski P, Bacolla A, Jaworski A, Wells RD. Nucleotide excision repair affects the stability of long transcribed (CTG*CAG) tracts in an orientation-dependent manner in Escherichia coli. Nucleic Acids Res 1999; 27:616-623.
112. Dixon MJ, Bhattacharyya S, Lahue RS. Genetic assays for triplet repeat instability in yeast. Methods Mol Biol 2004; 277:29-45.
113. Spiro C, Pelletier R, Rolfsmeier ML, et al. Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats. Mol Cell 1999; 4:1079-1085.
114. Liu Y, Kao HI, Bambara RA. Flap endonuclease 1: a central component of DNA metabolism. Annu Rev Biochem 2004; 73:589-615.
115. Liu Y, Zhang H, Veeraraghavan J, Bambara RA, Freudenreich CH. Saccharomyces cerevisiae flap endonuclease 1 uses flap equilibration to maintain triplet repeat stability. Mol Cell Biol 2004; 24:4049-4064.
116. Kovtun IV, Thornhill, AR, McMurray CT. Somatic deletion events occur during early embryonic development and modify the extent of CAG expansion in subsequent generations. Hum Mol Genet 2004; 13:3057-3068.
117. Spiegel R, La Spada, AR, Kress W, Fischbeck KH, Schmid W. Somatic stability of the expanded CAG trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Hum Mutat 1996; 8:32-37.
118. Wohrle D, Hennig I, Vogel W, Steinbach P. Mitotic stability of fragile X mutations in differentiated cells indicates early post-conceptional trinucleotide repeat expansion. Nat Genet 1993; 4:140-142.
119. Kovtun IV, Liu Y, Bjoras M, Klungland A, Wilson SH, McMurray CT. OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 2007; 447:447-452.
120. Farrell BT, Lahue RS. CAG/CTG repeat instability in cultured human astrocytes. Nucleic Acids Res 2006; 34:4495-4505.
121. Yang Z, Lau R, Marcadier JL, Chitayat D, Pearson CE. Replication inhibitors modulate instability of an expanded trinucleotide repeat at the myotonic dystrophy type 1 disease locus in human cells. Am J Hum Genet 2003; 73:1092-1010.
122. Wohrle D, Kennerknecht I, Wolf M, Enders H, Schwemmte S, Steinbach P. Heterogeneity of DM kinase repeat expansion in different fetal tissues and further expansion during cell proliferation in vitro: evidence for a casual involvement of methyl-directed DNA mismatch repair in triplet repeat stability. Hum Mol Genet 1995; 4:1147-1153.
123. Manley K, Pugh J, Messer A. Instability of the CAG repeat in immortalized fibroblast cell cultures from Huntington's disease transgenic mice. Brain Res 1999; 835:74-79.
124. Gomes-Pereira M, Fortune MT, Monckton DG. Mouse tissue culture models of unstable triplet repeats: in vitro selection for larger alleles, mutational expansion bias and tissue specificity, but no association with cell division rates. Hum Mol Genet 2001; 10:845-854.
125. Gu H, Marth JD, Orban PC, Mossmann H, Rajewsky K. Deletion of a DNA polymerase beta gene segment in T cells using cell type-specific gene targeting. Science 1994; 265:103-106.
126. Kucherlapati M, Yang K, Kuraguehi M, et al. Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression. Proc Natl Acad Sci USA 2002; 99:9924-9929.
127. Spiro C, McMurray CT. Nuclease-deficient FEN-1 blocks Rad51/ BRCA1-mediated repair and causes trinucleotide repeat instability. Mol Cell Biol 2003; 23:6063-6674.
128. van den Broek WJ, Nelen MR, van der Heijden GW, Wansink DG, Wieringa B. Fen1 does not control somatic hypermutability of the (CTG)(n)*(CAG)(n) repeat in a knock-in mouse model for DM1. FEBS Lett 2006; 580:5208-5214.
129. Kovtun IV, McMurray CT. Trinucleotide expansion in haploid germ cells by gap repair. Nat Genet 2001; 27:407-411.
130. Yoon SR, Dubeau L, de Young M, Wexler NS, Arnheim N. Huntington disease expansion mutations in humans can occur before meiosis is completed. Proc Natl Acad Sci USA 2003; 100:8834-8838.
131. Wheeler VC, Persichetti F, McNeil SM, et al. Factors associated with HD CAG repeat instability in Huntington disease. J Med Genet 2001; 44:695-701.
132. Savouret C, Garcia-Cordier C, Megret J, te Riele H, Junien C, Gourdon G. MSH2-dependent germinal CTG repeat expansions are produced continuously in spermatogonia from DM1 transgenic mice. Mol Cell Biol 2004; 24:629-637.
133. De Temmerman N, Sermon K, Seneca S, et al. Intergenerational instability of the expanded CTG repeat in the DMPK gene: studies in human gametes and preimplantation embryos. Am J Hum Genet 2004; 75:325-329.
134. Veitch NJ, Ennis M, McAbney JP; US-Venezuela Collaborative Research Project, Shelbourne PF, Monckton DG. Inherited CAG. CTG allele length is a major modifier of somatic mutation length variability in Huntington disease. DNA Repair (Amst) 2007; 6:789-789.
135. Seznec H, Lia-Baldini AS, Duros C, et al. Transgenic mice carrying large human genomic sequences with expanded CTG repeat mimic closely the DM CTG repeat intergenerational and somatic instability. Hum Mol Genet 2000; 9:1185-1194.
136. Monckton DG, Coolbaugh MI, Ashizawa KT, Siciliano MJ, Caskey CT. Hypermutable myotonic dystrophy CTG repeats in transgenic mice. Nat Genet 1997; 15:193-196.
137. Dixon MJ, Lahue RS. DNA elements important for CAG·CTG repeat thresholds in Saccharomyces cerevisiae. Nucleic Acids Res 2004; 32:1289-1297.
138. Brock GJ, Anderson NH, Monckton DG. Cis-acting modifiers of expanded CAG/CTG triplet repeat expandability: associations with flanking GC content and proximity to CpG islands. Hum Mol Genet 1999; 8:1061-1067.
139. Wöhrle D, Salat U, Gläser D, et al. Unusual mutations in high functioning fragile X males: apparent instability of expanded unmethylated CGG repeats. Med Genet 1998; 35:103-111.
140. Nichol K, Pearson CE. CpG Methylation Modifies the Genetic Stability of cloned repeat Genome Res 2002; 12:1246-1256.
141. 141Gorbunova V, Seluanov A, Mittelman D, Wilson JH. Genomewide demethylation destabilizes CTG.CAG trinucleotide repeats in mammalian cells. Hum Mol Genet 2004; 13:2979-2989.
142. Filippova GN, Thienes CP, Penn BH, et al. CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nat Genet 2001; 28:335-343.
143. Cleary JD, Nichol K, Wang YH, Pearson CE. Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells. Nat Genet 2002; 31:37-46.
144. Nenguke T, Aladjem MI, Gusella JF, et al. Candidate DNA replication initiation regions at human trinucleotide repeat disease loci. Hum Mol Genet 2003 12:1021-1028.
145. Chastain PD 2nd, Cohen SM, Brylawski BP, Cordeiro-Stone M, Kaufman DG. A late origin of DNA replication in the trinucleotide repeat region of the human FMR2 gene. Cell Cycle 2006; 5:869-872.
146. Gray SJ, Gerhardt J, Doerfler W, Small LE, Fanning E. An origin of DNA replication in the promoter region of the human fragile X mental retardation (FMR1) gene. Mol Cell Biol 2001 27:426-437.
147. Gourdon G, Radvanyi F, LiaAS, et al. Moderate intergenerational and somatic instability of a 55-CTG repeat in transgenic mice. Nat Genet 1997; 15:190-192.
148. Bingham PM, Scott MO, Wang S, et al. Stability of an expanded trinucleotide repeat in the androgen receptor gene in transgenic mice. Nat Genet 1995; 9:191-196.
149. Goldberg YP, Kalchman MA, Metzler M, et al. Absence of disease phenotype and intergenerational stability of the CAG repeat in transgenic mice expressing the human Huntington disease transcript. Hum Mol Genet 1996; 5:177-185.
150. Hodgson JG, Agopyan N, Gutekunst CA, et al. A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 1999; 23:181-192.
151. Burright EN, Clark HB, Servadio A, et al. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 1995; 82:937-948.
152. Gomes-Pereira M, Foiry L, Nicole A, et al. CTG trinucleotide repeat "big jumps": large expansions, small mice. PLoS Genet 2007; 3:e52.
153. Balakumaran BS, Freudenreich CH, Zakian VA. CGG/CCG repeats exhibit orientation-dependent instability and orientation-independent fragility in Saccharomyces cerevisiae. Hum Mol Genet 2000; 9:93-100.
154. Callahan JL, Andrews KJ, Zakian VA, Freudenreich CH. Mutations in yeast replication proteins that increase CAG/CTG expansions also increase repeat fragility. Mol Cell Biol 2003; 23:7849-7860.
155. Richards RI. Fragile and unstable chromosomes in cancer: Causes and consequences. Trends Genet 2001; 17:339-345.
156. Lemoine FJ, Degtyareva NP, Lobachev K, Petes TD. Chromosomal translocations in yeast induced by low levels of DNA polymerase a model for chromosome fragile sites. Cell 2005; 120:587-598.
157. Raveendranathan M, Chattopadhyay S, Bolon YT, Haworth J, Clarke DJ, Bielinsky AK. Genome-wide replication profiles of S-phase checkpoint mutants reveal fragile sites in yeast. EMBO J 2006; 25:3627-3639.
158. Bielinsky AK. Scarce but scary. Nat Genet 2007; 39:707-708.
159. Admire A, Shanks L, Danzl N, et al. Cycles of chromosome instability are associated with a fragile site and are increased by defects in DNA replication and checkpoint controls in yeast. Genes Dev 2006; 20:159-173.
160. Glover TW, Berger C, Coyle J, Echo B. DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum Genet 1984; 67:136-142.
161. Casper A, Nghiem P, Arlt MF, Glover TW. ATR regulates fragile site stability. Cell 2002; 111:779-789.
162. Glover TW, Stein CK Chromosome breakage and recombination at fragile sites. Am J Hum Genet 1988; 43:265-273.
163. Wang L, Paradee W, Mullins C, et al. Aphidicolin-induced FRA3B breakpoints cluster in two distinct regions. Genomics 1997;41:485-488.
164. Sutherland GR, Baker E, Richards RI. Fragile sites still breaking. Trends Genet 1998 14:501-506.
165. Lobachev KS, Gordenin DA, Resnick MA. The Mre11 complex is required for repair of hairpin-capped double-strand breaks and prevention of chromosome rearrangements. Cell 2002; 108:183-193
166. Zlotorynski E, Rahat A, Skaug J, et al. Molecular basis for expression of common and rare fragile sites. Mol Cell Biol 2003; 23:7143-7151.
167. Glover TW, ArIt MF, Casper AM, Durkin SG. Mechanisms of common fragile site instability. Hum Mol Genet 2005; 14:R197-R205.
168. Bielinsky AK. Replication origins: why do we need so many? Cell Cycle 2005; 2:307-309.
169. Cha RS, Kleckner N. ATR homolog Mecí promotes fork progression, thus averting breaks in replication slow zones. Science 2006; 297:602-606.
170. Rodriguez R, Meuth M. Chk1 and p21 cooperate to prevent apoptosis during DNA replication fork stress. Mol Biol Cell 2006; 17:402-412.
171. Arlt MF, Casper AM, Glover TW. Common fragile sites. Cytogenet Genome Res 2003; 100:92-100.
172. Cobb JA, Schleker T, Rojas V, Bjergbaek, Tercero TA, Gasser SM. Replisome instability, fork collapse, and gross chromosomal rearrangements arise synergistically from Mec1 kinase and RecQ helicase mutations. Genes Dev 2005; 19:3055-3069.
173. Lahiri M, Gustafson TL, Majors ER, Freudenreich CH. Expanded CAG repeats activate the DNA damage checkpoint pathway. Mol Cell 2004; 15:287-293.
174. Gomes-Pereira M, Fortune MT, Ingram L, McAbney JP, Monckton DG. Pms2 is a genetic enhancer of trinucleotide CAG.CTG repeat somatic mosaicism: implications for the mechanism of triplet repeat expansion. Hum Mol Genet 2004; 13:1815-1825.