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PMID: 10681451 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Meiotic instability of CAG repeat tracts occurs by double-strand break repair in yeast.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 5 ·2000-02-29 ·Pages 2134-9

Jankowski C, Nasar F, Nag DK

Abstract

Expansion of trinucleotide repeats is associated with a growing number of human diseases. The mechanism and timing of expansion of the repeat tract are poorly understood. In humans, trinucleotide repeats show extreme meiotic instability, and expansion of the repeat tract has been suggested to occur in the germ-line mitotic divisions or postmeiotically during early divisions of the embryo. Studies in model organisms have indicated that polymerase slippage plays a major role in the repeat tract instability and meiotic instability is severalfold higher than the mitotic instability. We show here that meiotic instability of the CAG/CTG repeat tract in yeast is associated with double-strand break (DSB) formation within the repeated sequences, and that the DSB formation is dependent on the meiotic recombination machinery. The DSB repair results in both expansions and contractions of the CAG repeat tract.

MeSH Terms
Alcohol Oxidoreductases Aminohydrolases DNA Damage DNA Repair DNA, Fungal Fungal Proteins/genetics Humans Meiosis Pyrophosphatases Saccharomyces cerevisiae/genetics Saccharomyces cerevisiae Proteins Transcription Factors/genetics Trinucleotide Repeats
Chemicals
DNA, Fungal Fungal Proteins Saccharomyces cerevisiae Proteins Transcription Factors Alcohol Oxidoreductases HIS4 protein, S cerevisiae Aminohydrolases Pyrophosphatases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Jankowski C
Molecular Genetics Program, Wadsworth Center, 120 New Scotland Avenue, Albany, NY 12201-2002, USA.
Nasar F
Nag D K
References (51)
51 references, click to expand
  1. Unequal meiotic recombination within tandem arrays of yeast ribosomal DNA genes.
    Cell. 1980 Mar;19(3):765-74 PMID: 6988084
  2. Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae.
    Microbiol Mol Biol Rev. 1999 Jun;63(2):349-404 PMID: 10357855
  3. Unequal crossing-over and gene conversion at the amplified CUP1 locus of yeast.
    Mol Gen Genet. 1990 Jul;222(2-3):304-10 PMID: 2274032
  4. Dynamic mutations: a new class of mutations causing human disease.
    Cell. 1992 Sep 4;70(5):709-12 PMID: 1516128
  5. Meiosis-induced double-strand break sites determined by yeast chromatin structure.
    Science. 1994 Jan 28;263(5146):515-8 PMID: 8290959
  6. Efficient copying of nonhomologous sequences from ectopic sites via P-element-induced gap repair.
    Mol Cell Biol. 1994 Mar;14(3):1613-25 PMID: 8114699
  7. Trinucleotide repeat expansions and human genetic disease.
    Bioessays. 1994 Apr;16(4):277-84 PMID: 8031305
  8. Preferential nucleosome assembly at DNA triplet repeats from the myotonic dystrophy gene.
    Science. 1994 Jul 29;265(5172):669-71 PMID: 8036515
  9. Changes in chromatin structure at recombination initiation sites during yeast meiosis.
    EMBO J. 1994 Dec 1;13(23):5754-63 PMID: 7988571
  10. Long DNA palindromes, cruciform structures, genetic instability and secondary structure repair.
    Bioessays. 1994 Dec;16(12):893-900 PMID: 7840768
  11. Meiosis-specific double-strand DNA breaks at the HIS4 recombination hot spot in the yeast Saccharomyces cerevisiae: control in cis and trans.
    Mol Cell Biol. 1995 Mar;15(3):1679-88 PMID: 7862159
  12. Trinucleotide repeats that expand in human disease form hairpin structures in vitro.
    Cell. 1995 May 19;81(4):533-40 PMID: 7758107
  13. Hairpins are formed by the single DNA strands of the fragile X triplet repeats: structure and biological implications.
    Proc Natl Acad Sci U S A. 1995 May 23;92(11):5199-203 PMID: 7761473
  14. Factors that affect the location and frequency of meiosis-induced double-strand breaks in Saccharomyces cerevisiae.
    Genetics. 1995 May;140(1):55-66 PMID: 7635308
  15. Mechanisms of DNA expansion.
    Chromosoma. 1995 Oct;104(1):2-13 PMID: 7587591
  16. Heteroduplex DNA formation and homolog pairing in yeast meiotic mutants.
    Genetics. 1995 Sep;141(1):75-86 PMID: 8536992
  17. Sequence non-specific double-strand breaks and interhomolog interactions prior to double-strand break formation at a meiotic recombination hot spot in yeast.
    EMBO J. 1995 Oct 16;14(20):5115-28 PMID: 7588640
  18. Single sperm analysis of the trinucleotide repeats in the Huntington's disease gene: quantification of the mutation frequency spectrum.
    Hum Mol Genet. 1995 Sep;4(9):1519-26 PMID: 8541834
  19. Mutation processes at human minisatellites.
    Electrophoresis. 1995 Sep;16(9):1577-85 PMID: 8582338
  20. Relationship between nuclease-hypersensitive sites and meiotic recombination hot spot activity at the HIS4 locus of Saccharomyces cerevisiae.
    Mol Cell Biol. 1996 May;16(5):2037-43 PMID: 8628269
  21. Alternative structures in duplex DNA formed within the trinucleotide repeats of the myotonic dystrophy and fragile X loci.
    Biochemistry. 1996 Apr 16;35(15):5041-53 PMID: 8664297
  22. Trinucleotide repeat expansion and human disease.
    Annu Rev Genet. 1995;29:703-28 PMID: 8825491
  23. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice.
    Cell. 1996 Nov 1;87(3):493-506 PMID: 8898202
  24. Orientation dependence of trinucleotide CAG repeat instability in Saccharomyces cerevisiae.
    Mol Cell Biol. 1996 Dec;16(12):6617-22 PMID: 8943315
  25. A novel mutation avoidance mechanism dependent on S. cerevisiae RAD27 is distinct from DNA mismatch repair.
    Cell. 1997 Jan 24;88(2):253-63 PMID: 9008166
  26. Characterization of the full fragile X syndrome mutation in fetal gametes.
    Nat Genet. 1997 Feb;15(2):165-9 PMID: 9020841
  27. DNA double-strand breaks caused by replication arrest.
    EMBO J. 1997 Jan 15;16(2):430-8 PMID: 9029161
  28. Genetic control of microsatellite stability.
    Mutat Res. 1997 Jan 31;383(1):61-70 PMID: 9042420
  29. Competition between adjacent meiotic recombination hotspots in the yeast Saccharomyces cerevisiae.
    Genetics. 1997 Mar;145(3):661-70 PMID: 9055076
  30. Stability of a CTG/CAG trinucleotide repeat in yeast is dependent on its orientation in the genome.
    Mol Cell Biol. 1997 Apr;17(4):2090-8 PMID: 9121457
  31. Destabilization of CAG trinucleotide repeat tracts by mismatch repair mutations in yeast.
    Hum Mol Genet. 1997 Mar;6(3):349-55 PMID: 9147637
  32. Big, bad minisatellites.
    Nat Genet. 1997 Apr;15(4):327-8 PMID: 9090372
  33. Instability of CAG and CTG trinucleotide repeats in Saccharomyces cerevisiae.
    Mol Cell Biol. 1997 Jun;17(6):3382-7 PMID: 9154837
  34. Trinucleotide repeats associated with human disease.
    Nucleic Acids Res. 1997 Jun 15;25(12):2245-54 PMID: 9171073
  35. Repeat expansion--all in a flap?
    Nat Genet. 1997 Jun;16(2):116-8 PMID: 9171819
  36. A 140-bp-long palindromic sequence induces double-strand breaks during meiosis in the yeast Saccharomyces cerevisiae.
    Genetics. 1997 Jul;146(3):835-47 PMID: 9215890
  37. Trinucleotide repeats affect DNA replication in vivo.
    Nat Genet. 1997 Nov;17(3):298-304 PMID: 9354793
  38. Expansions of CAG repeat tracts are frequent in a yeast mutant defective in Okazaki fragment maturation.
    Hum Mol Genet. 1998 Jan;7(1):69-74 PMID: 9384605
  39. Expansion and length-dependent fragility of CTG repeats in yeast.
    Science. 1998 Feb 6;279(5352):853-6 PMID: 9452383
  40. Expansions and contractions in a tandem repeat induced by double-strand break repair.
    Mol Cell Biol. 1998 Apr;18(4):2045-54 PMID: 9528777
  41. Double-strand break repair can lead to high frequencies of deletions within short CAG/CTG trinucleotide repeats.
    Mol Gen Genet. 1999 Jun;261(4-5):871-82 PMID: 10394925
  42. Stability of the human fragile X (CGG)(n) triplet repeat array in Saccharomyces cerevisiae deficient in aspects of DNA metabolism.
    Mol Cell Biol. 1999 Aug;19(8):5675-84 PMID: 10409756
  43. Genetic instabilities in (CTG.CAG) repeats occur by recombination.
    J Biol Chem. 1999 Aug 13;274(33):23468-79 PMID: 10438526
  44. Meiotic instability of human minisatellite CEB1 in yeast requires DNA double-strand breaks.
    Nat Genet. 1999 Nov;23(3):367-71 PMID: 10545956
  45. Destabilization of yeast micro- and minisatellite DNA sequences by mutations affecting a nuclease involved in Okazaki fragment processing (rad27) and DNA polymerase delta (pol3-t).
    Mol Cell Biol. 1998 May;18(5):2779-88 PMID: 9566897
  46. Instabilities of triplet repeats: factors and mechanisms.
    Results Probl Cell Differ. 1998;21:133-65 PMID: 9670316
  47. Orientation-dependent and sequence-specific expansions of CTG/CAG trinucleotide repeats in Saccharomyces cerevisiae.
    Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12438-43 PMID: 9770504
  48. Analysis of germline mutation spectra at the Huntington's disease locus supports a mitotic mutation mechanism.
    Hum Mol Genet. 1999 Feb;8(2):173-83 PMID: 9931325
  49. Triplet repeats form secondary structures that escape DNA repair in yeast.
    Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1504-9 PMID: 9990053
  50. Increased instability of human CTG repeat tracts on yeast artificial chromosomes during gametogenesis.
    Mol Cell Biol. 1999 Jun;19(6):4153-8 PMID: 10330155
  51. Palindromic sequences in heteroduplex DNA inhibit mismatch repair in yeast.
    Nature. 1989 Jul 27;340(6231):318-20 PMID: 2546083
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.040460297
Published
2000-02-29
Pages
2134-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC15766
Subset
IM
Grants
NIGMS NIH HHS · GM56266 · United States
External Links
PubMed source DOI: 10.1073/pnas.040460297 PMC Full Text View journal details
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