Skip to main content
NCBI home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 May;17(5):2851–2858. doi: 10.1128/mcb.17.5.2851

Microsatellite instability in yeast: dependence on repeat unit size and DNA mismatch repair genes.

E A Sia 1, R J Kokoska 1, M Dominska 1, P Greenwell 1, T D Petes 1
PMCID: PMC232137  PMID: 9111357

Abstract

We examined the stability of microsatellites of different repeat unit lengths in Saccharomyces cerevisiae strains deficient in DNA mismatch repair. The msh2 and msh3 mutations destabilized microsatellites with repeat units of 1, 2, 4, 5, and 8 bp; a poly(G) tract of 18 bp was destabilized several thousand-fold by the msh2 mutation and about 100-fold by msh3. The msh6 mutations destabilized microsatellites with repeat units of 1 and 2 bp but had no effect on microsatellites with larger repeats. These results argue that coding sequences containing repetitive DNA tracts will be preferred target sites for mutations in human tumors with mismatch repair defects. We find that the DNA mismatch repair genes destabilize microsatellites with repeat units from 1 to 13 bp but have no effect on the stability of minisatellites with repeat units of 16 or 20 bp. Our data also suggest that displaced loops on the nascent strand, resulting from DNA polymerase slippage, are repaired differently than loops on the template strand.

Full Text

The Full Text of this article is available as a PDF (173.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahn B. Y., Dornfeld K. J., Fagrelius T. J., Livingston D. M. Effect of limited homology on gene conversion in a Saccharomyces cerevisiae plasmid recombination system. Mol Cell Biol. 1988 Jun;8(6):2442–2448. doi: 10.1128/mcb.8.6.2442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alani E., Chi N. W., Kolodner R. The Saccharomyces cerevisiae Msh2 protein specifically binds to duplex oligonucleotides containing mismatched DNA base pairs and insertions. Genes Dev. 1995 Jan 15;9(2):234–247. doi: 10.1101/gad.9.2.234. [DOI] [PubMed] [Google Scholar]
  3. Alani E. The Saccharomyces cerevisiae Msh2 and Msh6 proteins form a complex that specifically binds to duplex oligonucleotides containing mismatched DNA base pairs. Mol Cell Biol. 1996 Oct;16(10):5604–5615. doi: 10.1128/mcb.16.10.5604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bishop D. K., Williamson M. S., Fogel S., Kolodner R. D. The role of heteroduplex correction in gene conversion in Saccharomyces cerevisiae. Nature. 1987 Jul 23;328(6128):362–364. doi: 10.1038/328362a0. [DOI] [PubMed] [Google Scholar]
  5. Carraway M., Marinus M. G. Repair of heteroduplex DNA molecules with multibase loops in Escherichia coli. J Bacteriol. 1993 Jul;175(13):3972–3980. doi: 10.1128/jb.175.13.3972-3980.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Das G., Consaul S., Sherman F. A highly revertible cyc1 mutant of yeast contains a small tandem duplication. Genetics. 1988 Sep;120(1):57–62. doi: 10.1093/genetics/120.1.57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fishel R. A., Siegel E. C., Kolodner R. Gene conversion in Escherichia coli. Resolution of heteroallelic mismatched nucleotides by co-repair. J Mol Biol. 1986 Mar 20;188(2):147–157. doi: 10.1016/0022-2836(86)90300-1. [DOI] [PubMed] [Google Scholar]
  8. Greene C. N., Jinks-Robertson S. Frameshift intermediates in homopolymer runs are removed efficiently by yeast mismatch repair proteins. Mol Cell Biol. 1997 May;17(5):2844–2850. doi: 10.1128/mcb.17.5.2844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Habraken Y., Sung P., Prakash L., Prakash S. Binding of insertion/deletion DNA mismatches by the heterodimer of yeast mismatch repair proteins MSH2 and MSH3. Curr Biol. 1996 Sep 1;6(9):1185–1187. doi: 10.1016/s0960-9822(02)70686-6. [DOI] [PubMed] [Google Scholar]
  10. Henderson S. T., Petes T. D. Instability of simple sequence DNA in Saccharomyces cerevisiae. Mol Cell Biol. 1992 Jun;12(6):2749–2757. doi: 10.1128/mcb.12.6.2749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Huang J., Papadopoulos N., McKinley A. J., Farrington S. M., Curtis L. J., Wyllie A. H., Zheng S., Willson J. K., Markowitz S. D., Morin P. APC mutations in colorectal tumors with mismatch repair deficiency. Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9049–9054. doi: 10.1073/pnas.93.17.9049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Iaccarino I., Palombo F., Drummond J., Totty N. F., Hsuan J. J., Modrich P., Jiricny J. MSH6, a Saccharomyces cerevisiae protein that binds to mismatches as a heterodimer with MSH2. Curr Biol. 1996 Apr 1;6(4):484–486. doi: 10.1016/s0960-9822(02)00516-x. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Johnson R. E., Kovvali G. K., Prakash L., Prakash S. Requirement of the yeast MSH3 and MSH6 genes for MSH2-dependent genomic stability. J Biol Chem. 1996 Mar 29;271(13):7285–7288. doi: 10.1074/jbc.271.13.7285. [DOI] [PubMed] [Google Scholar]
  15. Johnson R. E., Kovvali G. K., Prakash L., Prakash S. Requirement of the yeast RTH1 5' to 3' exonuclease for the stability of simple repetitive DNA. Science. 1995 Jul 14;269(5221):238–240. doi: 10.1126/science.7618086. [DOI] [PubMed] [Google Scholar]
  16. Kolodner R. Biochemistry and genetics of eukaryotic mismatch repair. Genes Dev. 1996 Jun 15;10(12):1433–1442. doi: 10.1101/gad.10.12.1433. [DOI] [PubMed] [Google Scholar]
  17. Kunkel T. A. Misalignment-mediated DNA synthesis errors. Biochemistry. 1990 Sep 4;29(35):8003–8011. doi: 10.1021/bi00487a001. [DOI] [PubMed] [Google Scholar]
  18. Levinson G., Gutman G. A. Slipped-strand mispairing: a major mechanism for DNA sequence evolution. Mol Biol Evol. 1987 May;4(3):203–221. doi: 10.1093/oxfordjournals.molbev.a040442. [DOI] [PubMed] [Google Scholar]
  19. Markowitz S., Wang J., Myeroff L., Parsons R., Sun L., Lutterbaugh J., Fan R. S., Zborowska E., Kinzler K. W., Vogelstein B. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995 Jun 2;268(5215):1336–1338. doi: 10.1126/science.7761852. [DOI] [PubMed] [Google Scholar]
  20. Marsischky G. T., Filosi N., Kane M. F., Kolodner R. Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair. Genes Dev. 1996 Feb 15;10(4):407–420. doi: 10.1101/gad.10.4.407. [DOI] [PubMed] [Google Scholar]
  21. Modrich P., Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem. 1996;65:101–133. doi: 10.1146/annurev.bi.65.070196.000533. [DOI] [PubMed] [Google Scholar]
  22. Palombo F., Iaccarino I., Nakajima E., Ikejima M., Shimada T., Jiricny J. hMutSbeta, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion loops in DNA. Curr Biol. 1996 Sep 1;6(9):1181–1184. doi: 10.1016/s0960-9822(02)70685-4. [DOI] [PubMed] [Google Scholar]
  23. Parker B. O., Marinus M. G. Repair of DNA heteroduplexes containing small heterologous sequences in Escherichia coli. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1730–1734. doi: 10.1073/pnas.89.5.1730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Strand M., Earley M. C., Crouse G. F., Petes T. D. Mutations in the MSH3 gene preferentially lead to deletions within tracts of simple repetitive DNA in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10418–10421. doi: 10.1073/pnas.92.22.10418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Streisinger G., Okada Y., Emrich J., Newton J., Tsugita A., Terzaghi E., Inouye M. Frameshift mutations and the genetic code. This paper is dedicated to Professor Theodosius Dobzhansky on the occasion of his 66th birthday. Cold Spring Harb Symp Quant Biol. 1966;31:77–84. doi: 10.1101/sqb.1966.031.01.014. [DOI] [PubMed] [Google Scholar]
  27. Tran H. T., Gordenin D. A., Resnick M. A. The prevention of repeat-associated deletions in Saccharomyces cerevisiae by mismatch repair depends on size and origin of deletions. Genetics. 1996 Aug;143(4):1579–1587. doi: 10.1093/genetics/143.4.1579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tran H. T., Keen J. D., Kricker M., Resnick M. A., Gordenin D. A. Hypermutability of homonucleotide runs in mismatch repair and DNA polymerase proofreading yeast mutants. Mol Cell Biol. 1997 May;17(5):2859–2865. doi: 10.1128/mcb.17.5.2859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Umar A., Boyer J. C., Kunkel T. A. DNA loop repair by human cell extracts. Science. 1994 Nov 4;266(5186):814–816. doi: 10.1126/science.7973637. [DOI] [PubMed] [Google Scholar]
  30. Wierdl M., Greene C. N., Datta A., Jinks-Robertson S., Petes T. D. Destabilization of simple repetitive DNA sequences by transcription in yeast. Genetics. 1996 Jun;143(2):713–721. doi: 10.1093/genetics/143.2.713. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES