Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer (original) (raw)

. 1997 Apr;60(4):879–890.

Abstract

Two recent lines of evidence raise the possibility that instability in germ-line or somatic cells arises by a common mechanism that involves defective mismatch repair. Mutations in mismatch-repair proteins are known to cause instability in hereditary nonpolyposis colorectal cancer, instability that is physically similar to germ-line instability observed in Huntington disease (HD). Furthermore, both germ-line and somatic-cell instability are likely to be mitotic defects, the former occurring early in embryogenesis. To test the hypothesis that defective repair is a common prerequisite for instability, we have utilized two disease groups that represent different instability "conditions." Germ-line instability within simple tandem repeats (STR) at 10 loci in 29 HD families were compared with somatic instability at the same loci in 26 colon cancer (CC) patients with identified or suspected defects in mismatch-repair enzymes. HD is known to be caused by expansion within the CAG repeat of the locus, but the extent or pattern of STR instability outside this region has not been examined systematically. We find a distinctly different pattern of STR mutation in the two disease groups, suggesting different mechanisms. Instability in HD is generally confined to a single locus, whereas instability is widespread for the same loci in CC. Our data do not support a causative role for defective mismatch-repair enzymes in instability associated with HD; rather, our data are consistent with a model in which DNA structure may inhibit normal mismatch repair at the expansion site.

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Selected References

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  1. Aaltonen L. A., Peltomäki P., Leach F. S., Sistonen P., Pylkkänen L., Mecklin J. P., Järvinen H., Powell S. M., Jen J., Hamilton S. R. Clues to the pathogenesis of familial colorectal cancer. Science. 1993 May 7;260(5109):812–816. doi: 10.1126/science.8484121. [DOI] [PubMed] [Google Scholar]
  2. Ashley C. T., Jr, Warren S. T. Trinucleotide repeat expansion and human disease. Annu Rev Genet. 1995;29:703–728. doi: 10.1146/annurev.ge.29.120195.003415. [DOI] [PubMed] [Google Scholar]
  3. Baker S. M., Bronner C. E., Zhang L., Plug A. W., Robatzek M., Warren G., Elliott E. A., Yu J., Ashley T., Arnheim N. Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis. Cell. 1995 Jul 28;82(2):309–319. doi: 10.1016/0092-8674(95)90318-6. [DOI] [PubMed] [Google Scholar]
  4. Bates G., Lehrach H. Trinucleotide repeat expansions and human genetic disease. Bioessays. 1994 Apr;16(4):277–284. doi: 10.1002/bies.950160411. [DOI] [PubMed] [Google Scholar]
  5. Bronner C. E., Baker S. M., Morrison P. T., Warren G., Smith L. G., Lescoe M. K., Kane M., Earabino C., Lipford J., Lindblom A. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature. 1994 Mar 17;368(6468):258–261. doi: 10.1038/368258a0. [DOI] [PubMed] [Google Scholar]
  6. Brook J. D., McCurrach M. E., Harley H. G., Buckler A. J., Church D., Aburatani H., Hunter K., Stanton V. P., Thirion J. P., Hudson T. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell. 1992 Feb 21;68(4):799–808. doi: 10.1016/0092-8674(92)90154-5. [DOI] [PubMed] [Google Scholar]
  7. Campuzano V., Montermini L., Moltò M. D., Pianese L., Cossée M., Cavalcanti F., Monros E., Rodius F., Duclos F., Monticelli A. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996 Mar 8;271(5254):1423–1427. doi: 10.1126/science.271.5254.1423. [DOI] [PubMed] [Google Scholar]
  8. Carbonnaux C., van der Marel G. A., van Boom J. H., Guschlbauer W., Fazakerley G. V. Solution structure of an oncogenic DNA duplex containing a G.A mismatch. Biochemistry. 1991 Jun 4;30(22):5449–5458. doi: 10.1021/bi00236a018. [DOI] [PubMed] [Google Scholar]
  9. Chen X., Mariappan S. V., Catasti P., Ratliff R., Moyzis R. K., Laayoun A., Smith S. S., Bradbury E. M., Gupta G. 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):5199–5203. doi: 10.1073/pnas.92.11.5199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cunningham J., Lust J. A., Schaid D. J., Bren G. D., Carpenter H. A., Rizza E., Kovach J. S., Thibodeau S. N. Expression of p53 and 17p allelic loss in colorectal carcinoma. Cancer Res. 1992 Apr 1;52(7):1974–1980. [PubMed] [Google Scholar]
  11. Dolinnaya N. G., Fresco J. R. Single-stranded nucleic acid helical secondary structure stabilized by ionic bonds: d(A(+)-G)10. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9242–9246. doi: 10.1073/pnas.89.19.9242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fishel R., Lescoe M. K., Rao M. R., Copeland N. G., Jenkins N. A., Garber J., Kane M., Kolodner R. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell. 1993 Dec 3;75(5):1027–1038. doi: 10.1016/0092-8674(93)90546-3. [DOI] [PubMed] [Google Scholar]
  13. Frank-Kamenetskii M. D., Mirkin S. M. Triplex DNA structures. Annu Rev Biochem. 1995;64:65–95. doi: 10.1146/annurev.bi.64.070195.000433. [DOI] [PubMed] [Google Scholar]
  14. Gacy A. M., Goellner G., Juranić N., Macura S., McMurray C. T. Trinucleotide repeats that expand in human disease form hairpin structures in vitro. Cell. 1995 May 19;81(4):533–540. doi: 10.1016/0092-8674(95)90074-8. [DOI] [PubMed] [Google Scholar]
  15. Gacy A. M., McMurray C. T. Hairpin formation within the human enkephalin enhancer region. 1. Kinetic analysis. Biochemistry. 1994 Oct 4;33(39):11951–11959. doi: 10.1021/bi00205a034. [DOI] [PubMed] [Google Scholar]
  16. Goldberg Y. P., Kremer B., Andrew S. E., Theilmann J., Graham R. K., Squitieri F., Telenius H., Adam S., Sajoo A., Starr E. Molecular analysis of new mutations for Huntington's disease: intermediate alleles and sex of origin effects. Nat Genet. 1993 Oct;5(2):174–179. doi: 10.1038/ng1093-174. [DOI] [PubMed] [Google Scholar]
  17. Goldberg Y. P., McMurray C. T., Zeisler J., Almqvist E., Sillence D., Richards F., Gacy A. M., Buchanan J., Telenius H., Hayden M. R. Increased instability of intermediate alleles in families with sporadic Huntington disease compared to similar sized intermediate alleles in the general population. Hum Mol Genet. 1995 Oct;4(10):1911–1918. doi: 10.1093/hmg/4.10.1911. [DOI] [PubMed] [Google Scholar]
  18. Gonzalez G. A., Yamamoto K. K., Fischer W. H., Karr D., Menzel P., Biggs W., 3rd, Vale W. W., Montminy M. R. A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence. Nature. 1989 Feb 23;337(6209):749–752. doi: 10.1038/337749a0. [DOI] [PubMed] [Google Scholar]
  19. Greene K. L., Jones R. L., Li Y., Robinson H., Wang A. H., Zon G., Wilson W. D. Solution structure of a GA mismatch DNA sequence, d(CCATGAATGG)2, determined by 2D NMR and structural refinement methods. Biochemistry. 1994 Feb 8;33(5):1053–1062. doi: 10.1021/bi00171a003. [DOI] [PubMed] [Google Scholar]
  20. Heale S. M., Petes T. D. The stabilization of repetitive tracts of DNA by variant repeats requires a functional DNA mismatch repair system. Cell. 1995 Nov 17;83(4):539–545. doi: 10.1016/0092-8674(95)90093-4. [DOI] [PubMed] [Google Scholar]
  21. Honchel R., Halling K. C., Thibodeau S. N. Genomic instability in neoplasia. Semin Cell Biol. 1995 Feb;6(1):45–52. doi: 10.1016/1043-4682(95)90014-4. [DOI] [PubMed] [Google Scholar]
  22. Igarashi S., Takiyama Y., Cancel G., Rogaeva E. A., Sasaki H., Wakisaka A., Zhou Y. X., Takano H., Endo K., Sanpei K. Intergenerational instability of the CAG repeat of the gene for Machado-Joseph disease (MJD1) is affected by the genotype of the normal chromosome: implications for the molecular mechanisms of the instability of the CAG repeat. Hum Mol Genet. 1996 Jul;5(7):923–932. doi: 10.1093/hmg/5.7.923. [DOI] [PubMed] [Google Scholar]
  23. Ionov Y., Peinado M. A., Malkhosyan S., Shibata D., Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993 Jun 10;363(6429):558–561. doi: 10.1038/363558a0. [DOI] [PubMed] [Google Scholar]
  24. Jaworski A., Rosche W. A., Gellibolian R., Kang S., Shimizu M., Bowater R. P., Sinden R. R., Wells R. D. Mismatch repair in Escherichia coli enhances instability of (CTG)n triplet repeats from human hereditary diseases. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11019–11023. doi: 10.1073/pnas.92.24.11019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jeffreys A. J., Tamaki K., MacLeod A., Monckton D. G., Neil D. L., Armour J. A. Complex gene conversion events in germline mutation at human minisatellites. Nat Genet. 1994 Feb;6(2):136–145. doi: 10.1038/ng0294-136. [DOI] [PubMed] [Google Scholar]
  26. Kang S. M., Wohlrab F., Wells R. D. Metal ions cause the isomerization of certain intramolecular triplexes. J Biol Chem. 1992 Jan 15;267(2):1259–1264. [PubMed] [Google Scholar]
  27. Kawaguchi Y., Okamoto T., Taniwaki M., Aizawa M., Inoue M., Katayama S., Kawakami H., Nakamura S., Nishimura M., Akiguchi I. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994 Nov;8(3):221–228. doi: 10.1038/ng1194-221. [DOI] [PubMed] [Google Scholar]
  28. Koide R., Ikeuchi T., Onodera O., Tanaka H., Igarashi S., Endo K., Takahashi H., Kondo R., Ishikawa A., Hayashi T. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet. 1994 Jan;6(1):9–13. doi: 10.1038/ng0194-9. [DOI] [PubMed] [Google Scholar]
  29. Kramer P. R., Pearson C. E., Sinden R. R. Stability of triplet repeats of myotonic dystrophy and fragile X loci in human mutator mismatch repair cell lines. Hum Genet. 1996 Aug;98(2):151–157. doi: 10.1007/s004390050179. [DOI] [PubMed] [Google Scholar]
  30. Kremer B., Almqvist E., Theilmann J., Spence N., Telenius H., Goldberg Y. P., Hayden M. R. Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes. Am J Hum Genet. 1995 Aug;57(2):343–350. [PMC free article] [PubMed] [Google Scholar]
  31. Kremer E. J., Pritchard M., Lynch M., Yu S., Holman K., Baker E., Warren S. T., Schlessinger D., Sutherland G. R., Richards R. I. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science. 1991 Jun 21;252(5013):1711–1714. doi: 10.1126/science.1675488. [DOI] [PubMed] [Google Scholar]
  32. Kunkel L. M., Smith K. D., Boyer S. H., Borgaonkar D. S., Wachtel S. S., Miller O. J., Breg W. R., Jones H. W., Jr, Rary J. M. Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc Natl Acad Sci U S A. 1977 Mar;74(3):1245–1249. doi: 10.1073/pnas.74.3.1245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kunkel T. A. Nucleotide repeats. Slippery DNA and diseases. Nature. 1993 Sep 16;365(6443):207–208. doi: 10.1038/365207a0. [DOI] [PubMed] [Google Scholar]
  34. La Spada A. R., Wilson E. M., Lubahn D. B., Harding A. E., Fischbeck K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991 Jul 4;352(6330):77–79. doi: 10.1038/352077a0. [DOI] [PubMed] [Google Scholar]
  35. Leach F. S., Nicolaides N. C., Papadopoulos N., Liu B., Jen J., Parsons R., Peltomäki P., Sistonen P., Aaltonen L. A., Nyström-Lahti M. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell. 1993 Dec 17;75(6):1215–1225. doi: 10.1016/0092-8674(93)90330-s. [DOI] [PubMed] [Google Scholar]
  36. Leeflang E. P., Zhang L., Tavaré S., Hubert R., Srinidhi J., MacDonald M. E., Myers R. H., de Young M., Wexler N. S., Gusella J. F. 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):1519–1526. doi: 10.1093/hmg/4.9.1519. [DOI] [PubMed] [Google Scholar]
  37. Litt M., Luty J. A. A hypervariable microsatellite revealed by in vitro amplification of a dinucleotide repeat within the cardiac muscle actin gene. Am J Hum Genet. 1989 Mar;44(3):397–401. [PMC free article] [PubMed] [Google Scholar]
  38. MacDonald M. E., Novelletto A., Lin C., Tagle D., Barnes G., Bates G., Taylor S., Allitto B., Altherr M., Myers R. The Huntington's disease candidate region exhibits many different haplotypes. Nat Genet. 1992 May;1(2):99–103. doi: 10.1038/ng0592-99. [DOI] [PubMed] [Google Scholar]
  39. McMurray C. T. Mechanisms of DNA expansion. Chromosoma. 1995 Oct;104(1):2–13. doi: 10.1007/BF00352220. [DOI] [PubMed] [Google Scholar]
  40. Mitas M., Yu A., Dill J., Kamp T. J., Chambers E. J., Haworth I. S. Hairpin properties of single-stranded DNA containing a GC-rich triplet repeat: (CTG)15. Nucleic Acids Res. 1995 Mar 25;23(6):1050–1059. doi: 10.1093/nar/23.6.1050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Nicolaides N. C., Papadopoulos N., Liu B., Wei Y. F., Carter K. C., Ruben S. M., Rosen C. A., Haseltine W. A., Fleischmann R. D., Fraser C. M. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature. 1994 Sep 1;371(6492):75–80. doi: 10.1038/371075a0. [DOI] [PubMed] [Google Scholar]
  42. Orr H. T., Chung M. Y., Banfi S., Kwiatkowski T. J., Jr, Servadio A., Beaudet A. L., McCall A. E., Duvick L. A., Ranum L. P., Zoghbi H. Y. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993 Jul;4(3):221–226. doi: 10.1038/ng0793-221. [DOI] [PubMed] [Google Scholar]
  43. Papadopoulos N., Nicolaides N. C., Wei Y. F., Ruben S. M., Carter K. C., Rosen C. A., Haseltine W. A., Fleischmann R. D., Fraser C. M., Adams M. D. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994 Mar 18;263(5153):1625–1629. doi: 10.1126/science.8128251. [DOI] [PubMed] [Google Scholar]
  44. Parsons R., Li G. M., Longley M. J., Fang W. H., Papadopoulos N., Jen J., de la Chapelle A., Kinzler K. W., Vogelstein B., Modrich P. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell. 1993 Dec 17;75(6):1227–1236. doi: 10.1016/0092-8674(93)90331-j. [DOI] [PubMed] [Google Scholar]
  45. Paulson H. L., Fischbeck K. H. Trinucleotide repeats in neurogenetic disorders. Annu Rev Neurosci. 1996;19:79–107. doi: 10.1146/annurev.ne.19.030196.000455. [DOI] [PubMed] [Google Scholar]
  46. Sears L. E., Moran L. S., Kissinger C., Creasey T., Perry-O'Keefe H., Roskey M., Sutherland E., Slatko B. E. CircumVent thermal cycle sequencing and alternative manual and automated DNA sequencing protocols using the highly thermostable VentR (exo-) DNA polymerase. Biotechniques. 1992 Oct;13(4):626–633. [PubMed] [Google Scholar]
  47. Shibata D., Peinado M. A., Ionov Y., Malkhosyan S., Perucho M. Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation. Nat Genet. 1994 Mar;6(3):273–281. doi: 10.1038/ng0394-273. [DOI] [PubMed] [Google Scholar]
  48. Snow K., Doud L. K., Hagerman R., Pergolizzi R. G., Erster S. H., Thibodeau S. N. Analysis of a CGG sequence at the FMR-1 locus in fragile X families and in the general population. Am J Hum Genet. 1993 Dec;53(6):1217–1228. [PMC free article] [PubMed] [Google Scholar]
  49. Spiro C., Richards J. P., Chandrasekaran S., Brennan R. G., McMurray C. T. Secondary structure creates mismatched base pairs required for high-affinity binding of cAMP response element-binding protein to the human enkephalin enhancer. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4606–4610. doi: 10.1073/pnas.90.10.4606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Strand M., Prolla T. A., Liskay R. M., Petes T. D. Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature. 1993 Sep 16;365(6443):274–276. doi: 10.1038/365274a0. [DOI] [PubMed] [Google Scholar]
  51. Sutherland G. R., Richards R. I. Simple tandem DNA repeats and human genetic disease. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3636–3641. doi: 10.1073/pnas.92.9.3636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Thibodeau S. N., Bren G., Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993 May 7;260(5109):816–819. doi: 10.1126/science.8484122. [DOI] [PubMed] [Google Scholar]
  53. Vasen H. F., Mecklin J. P., Khan P. M., Lynch H. T. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. 1991 May;34(5):424–425. doi: 10.1007/BF02053699. [DOI] [PubMed] [Google Scholar]
  54. Weber J. L., May P. E. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet. 1989 Mar;44(3):388–396. [PMC free article] [PubMed] [Google Scholar]
  55. Weber J. L., Wong C. Mutation of human short tandem repeats. Hum Mol Genet. 1993 Aug;2(8):1123–1128. doi: 10.1093/hmg/2.8.1123. [DOI] [PubMed] [Google Scholar]
  56. Zhu L., Chou S. H., Xu J., Reid B. R. Structure of a single-cytidine hairpin loop formed by the DNA triplet GCA. Nat Struct Biol. 1995 Nov;2(11):1012–1017. doi: 10.1038/nsb1195-1012. [DOI] [PubMed] [Google Scholar]
  57. de Wind N., Dekker M., Berns A., Radman M., te Riele H. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell. 1995 Jul 28;82(2):321–330. doi: 10.1016/0092-8674(95)90319-4. [DOI] [PubMed] [Google Scholar]