Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Report
  • Published:

Elevated mutant frequencies and predominance of G:C to A:T transition mutations in Msh6−/− small intestinal epithelium

Oncogene volume 21, pages 7126–7130 (2002)Cite this article

Abstract

The DNA mismatch repair (MMR) system is primarily responsible for purging newly synthesized DNA of errors incurred during semi-conservative replication. Lesion recognition is initially carried out by one of two heterodimeric protein complexes, MutSα or MutSβ. While the former, comprised of MSH2 and MSH6, recognizes mispairs as well as short (1–2 nucleotide) insertions/deletions (IDLs), the latter, made up of MSH2 and MSH3, is primarily responsible for recognizing 2–6 nucleotide IDLs. As most of the functional information on these heterodimers is derived from in vitro studies, it was of interest to study the in vivo consequences of a lack of MutSα. To this end, Big Blue™ mice, that carry a lacI+ transgenic λ shuttle-phage mutational reporter, were crossed with Msh6−/− mice to evaluate the specific contribution of MutSα to genome integrity. Consistent with the importance of MutSα in lesion surveillance, small intestine epithelial cell DNA derived from lacI+ Msh6−/− mice exhibited striking increases (average of 41-fold) in spontaneous mutant frequencies. Furthermore, the lacI gene mutation spectrum was dominated by G:C to A:T transitions, highlighting the critical importance of the MutSα complex in suppressing this frequently observed type of spontaneous mutation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Abbreviations

MMR:

mismatch repair

MSH:

MutS homolog

IDLs:

insertion/deletion loops

References

  • Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R . 1996 Proc. Natl. Acad. Sci. USA 93: 13629–13634

  • Andrew SE, Pownall S, Fox J, Hsiao L, Hambleton J, Penney JE, Kohler SW, Jirik FR . 1996 Mutat. Res. 357: 57–66

  • Andrew SE, Reitmair AH, Fox J, Hsiao L, Francis A, McKinnon M, Mak TW, Jirik FR . 1997 Oncogene 15: 123–129

  • Andrew SE, McKinnon M, Cheng BS, Francis A, Penney J, Reitmair AH, Mak TW, Jirik FR . 1998 Proc. Natl. Acad. Sci. USA 95: 1126–1130

  • Andrew SE, Xu XS, Baross-Francis A, Narayanan L, Milhausen K, Liskay RM, Jirik FR, Glazer PM . 2000 Carcinogenesis 21: 1291–1295

  • Aquilina G, Bignami M . 2001 J. Cell. Physiol. 187: 145–154

  • Baker SM, Bronner CE, Zhang L, Plug AW, Robatzek M, Warren G, Elliott EA, Yu J, Ashley T, Arnheim N, Flavell RA, Liskay RM . 1995 Cell 82: 309–319

  • Baker SM, Plug AW, Prolla TA, Bronner CE, Harris AC, Yao X, Christie DM, Monell C, Arnheim N, Bradley A, Ashley T, Liskay RM . 1996 Nat. Genet. 13: 336–342

  • Baross-Francis A, Andrew SE, Penney JE, Jirik FR . 1998 Proc. Natl. Acad. Sci. USA 95: 8739–8743

  • Baross-Francis A, Makhani N, Liskay RM, Jirik FR . 2001 Oncogene 20: 619–625

  • Buermeyer AB, Deschenes SM, Baker SM, Liskay RM . 1999 Annu. Rev. Genet. 33: 533–564

  • Cariello NF, Piegorsch WW, Adams WT, Skopek TR . 1994 Carcinogenesis 15: 2281–2285

  • Cariello NF, Gorelick NJ . 1996 Environ. Mol. Mutagen. 28: 397–404

  • Corpet F . 1988 Nucleic Acids Res. 16: 10881–10890

  • Cosentino L, Heddle JA . 2000 Mutat. Res. 454: 1–10

  • de Wind N, Dekker M, Berns A, Radman M, te Riele H . 1995 Cell 82: 321–330

  • de Wind N, Dekker M, Claij N, Jansen L, van Klink Y, Radman M, Riggins G, van der Valk M, van't Wout K, te Riele H . 1999 Nat. Genet. 23: 359–362

  • Drummond JT, Genschel J, Wolf E, Modrich P . 1997 Proc. Natl. Acad. Sci. USA 94: 10144–10149

  • Dycaico MJ, Provost GS, Kretz PL, Ransom SL, Moores JC, Short JM . 1994 Mutat. Res. 307: 461–478

  • Edelmann W, Cohen PE, Kane M, Lau K, Morrow B, Bennett S, Umar A, Kunkel T, Cattoretti G, Chaganti R, Pollard JW, Kolodner RD, Kucherlapati R . 1996 Cell 85: 1125–1134

  • Edelmann W, Umar A, Yang K, Heyer J, Kucherlapati M, Lia M, Kneitz B, Avdievich E, Fan K, Wong E, Crouse G, Kunkel T, Lipkin M, Kolodner RD, Kucherlapati R . 2000 Cancer Res. 60: 803–807

  • Edelmann W, Yang K, Umar A, Heyer J, Lau K, Fan K, Liedtke W, Cohen PE, Kane MF, Lipford JR, Yu N, Crouse GF, Pollard JW, Kunkel T, Lipkin M, Kolodner R, Kucherlapati R . 1997 Cell 91: 467–477

  • Genschel J, Littman SJ, Drummond JT, Modrich P . 1998 J. Biol. Chem. 273: 19895–19901

  • Jiricny J, Nystrom-Lahti M . 2000 Curr. Opin. Genet. Dev. 10: 157–161

  • Kolodner R . 1996 Genes. Dev. 10: 1433–1442

  • Kolodner RD, Tytell JD, Schmeits JL, Kane MF, Gupta RD, Weger J, Wahlberg S, Fox EA, Peel D, Ziogas A, Garber JE, Syngal S, Anton-Culver H, Li FP . 1999 Cancer Res. 59: 5068–5074

  • Kuraguchi M, Yang K, Wong E, Avdievich E, Fan K, Kolodner RD, Lipkin M, Brown AM, Kucherlapati R, Edelmann W . 2001 Cancer Res. 61: 7934–7942

  • Marra G, Iaccarino I, Lettieri T, Roscilli G, Delmastro P, Jiricny J . 1998 Proc. Natl. Acad. Sci. USA 95: 8568–8573

  • Marra G, Schar P . 1999 Biochem. J. 338: 1–13

  • Mirsalis JC, Provost GS, Matthews CD, Hamner RT, Schindler JE, O'Loughlin KG, MacGregor JT, Short JM . 1993 Mutagenesis 8: 265–271

  • Modrich P . 1991 Annu. Rev. Genet. 25: 229–253

  • Modrich P, Lahue R . 1996 Annu. Rev. Biochem. 65: 101–133

  • Monroe JJ, Manjanatha MG, Skopek TR . 2001 Mutat. Res. 476: 1–11

  • Narayanan L, Fritzell JA, Baker SM, Liskay RM, Glazer PM . 1997 Proc. Natl. Acad. Sci. USA 94: 3122–3127

  • Palombo F, Gallinari P, Iaccarino I, Lettieri T, Hughes M, D'Arrigo A, Truong O, Hsuan JJ, Jiricny J . 1995 Science 268: 1912–1914

  • Palombo F, Iaccarino I, Nakajima E, Ikejima M, Shimada T, Jiricny J . 1996 Curr. Biol. 6: 1181–1184

  • Peltomaki P . 2001 Hum. Mol. Genet. 10: 735–740

  • Provost GS, Kretz PL, Hamner RT, Matthews CD, Rogers BJ, Lundberg KS, Dycaico MJ, Short JM . 1993 Mutat. Res. 288: 133–149

  • Reitmair AH, Schmits R, Ewel A, Bapat B, Redston M, Mitri A, Waterhouse P, Mittrucker HW, Wakeham A, Liu B, Thomason A, Griesser H, Gallinger S, Ballhausen WG, Fishel R, Mak TW . 1995 Nat. Genet. 11: 64–70

  • Skopek T, Marino D, Kort K, Miller J, Trumbauer M, Gopal S, Chen H . 1998 Mutat. Res. 400: 77–88

  • Umar A, Risinger JI, Glaab WE, Tindall KR, Barrett JC, Kunkel TA . 1998 Genetics 148: 1637–1646

  • Wang TF, Kleckner N, Hunter N . 1999 Proc. Natl. Acad. Sci. USA 96: 13914–13919

  • Zhang S, Glickman BW, de Boer JG . 2001 Environ. Mol. Mutagen. 37: 141–146

Download references

Acknowledgements

We are grateful to S Lines for maintaining the animal colony and help in genotyping. This study was supported by the National Cancer Institute of Canada with funds from the Canadian Cancer Society (to FR Jirik), and by the Alberta Heritage Foundation for Medical Research (AHFMR) (to FR Jirik) and NIH grant number CA 76329 (to W Edelmann). FR Jirik was the recipient of AHFMR Scientist and Canada Research Chair awards.

Author information

Author notes

  1. Agnes Baross

    Present address: British Columbia Cancer Research Centre, 601 West 10th Avenue, Vancouver, V5Z 4E6, BC, Canada

  2. Sean C Mark and Linda E Sandercock: Sean C Mark and Linda E Sandercock contributed equally to this work

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, T2N 4N1, Alberta, Canada

    Sean C Mark, Linda E Sandercock, H Artee Luchman, Agnes Baross & Frank R Jirik

  2. Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY10461, New York, USA

    Winfried Edelmann

Authors
  1. Sean C Mark
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Linda E Sandercock
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Artee Luchman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Agnes Baross
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Winfried Edelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Frank R Jirik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank R Jirik.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mark, S., Sandercock, L., Luchman, H. et al. Elevated mutant frequencies and predominance of G:C to A:T transition mutations in Msh6−/− small intestinal epithelium. Oncogene 21, 7126–7130 (2002). https://doi.org/10.1038/sj.onc.1205861

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205861

Keywords

This article is cited by

Search

Advanced search

Quick links