Abstract
The CTG repeat involved in myotonic dystrophy is one of the most unstable trinucleotide repeats. However, the molecular mechanisms underlying this particular form of genetic instability—biased towards expansions—have not yet been completely elucidated. We previously showed, with highly unstable CTG repeat arrays in DM1 transgenic mice, that Msh2 is required for the formation of intergenerational and somatic expansions. To identify the partners of Msh2 in the formation of intergenerational CTG repeat expansions, we investigated the involvement of Msh3 and Msh6, partners of Msh2 in mismatch repair. Transgenic mice with CTG expansions were crossed with Msh3- or Msh6-deficient mice and CTG repeats were analysed after maternal and paternal transmissions. We demonstrated that Msh3 but not Msh6 plays also a key role in the formation of expansions over successive generation. Furthermore, the absence of one Msh3 allele was sufficient to decrease the formation of expansions, indicating that Msh3 is rate-limiting in this process. In the absence of Msh6, the frequency of expansions decreased only in maternal transmissions. However, the significantly lower levels of Msh2 and Msh3 proteins in Msh6 -/- ovaries suggest that the absence of Msh6 may have an indirect effect.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R (1996) hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc Natl Acad Sci USA 93:13629–13634
van den Broek WJ, Nelen MR, Wansink DG, Coerwinkel MM, te Riele H, Groenen PJ, Wieringa B (2002) Somatic expansion behaviour of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch- repair proteins. Hum Mol Genet 11:191–198
Chang DK, Ricciardiello L, Goel A, Chang CL, Boland CR (2000) Steady-state regulation of the human DNA mismatch repair system. J Biol Chem 275:29178
Cleary JD, Pearson CE (2003) The contribution of cis-elements to disease-associated repeat instability: clinical and experimental evidence. Cytogenet Genome Res 100:25–55
Cleary JD, Pearson CE (2005) Replication fork dynamics and dynamic mutations: the fork-shift model of repeat instability. Trends Genet 21:272–280
Drummond JT (1999) Genomic amplification of the human DHFR/MSH3 locus remodels mismatch recognition and repair activities. Adv Enzyme Regul 39:129–141
Fortune MT, Vassilopoulos C, Coolbaugh MI, Siciliano MJ, Monckton DG (2000) Dramatic, expansion-biased, age-dependent, tissue-specific somatic mosaicism in a transgenic mouse model of triplet repeat instability. Hum Mol Genet 9:439–445
Gomes-Pereira M, Fortune MT, Monckton DG (2001) 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 10:845–854
Gomes-Pereira M, Fortune MT, Ingram L, McAbney JP, Monckton DG (2004) Pms2 is a genetic enhancer of trinucleotide CAG.CTG repeat somatic mosaicism: implications for the mechanism of triplet repeat expansion. Hum Mol Genet 13:1815–1825
Harper PS (2001) Myotonic dystrophy, 3rd edn. London, Philadelphia
Jeffreys AJ, Tamaki K, MacLeod A, Monckton DG, Neil DL, Armour JA (1994) Complex gene conversion events in germline mutation at human minisatellites. Nat Genet 6:136–145
Kovtun IV, McMurray CT (2001) Trinucleotide expansion in haploid germ cells by gap repair. Nat Genet 27:407–411
Kovtun IV, Thornhill AR, McMurray CT (2004) Somatic deletion events occur during early embryonic development and modify the extent of CAG expansion in subsequent generations. Hum Mol Genet 13:3057–3068
Lahue RS, Slater DL (2003) DNA repair and trinucleotide repeat instability. Front Biosci 8:s653–s665
Lia A, Seznec H, Hofmann-Radvanyi H, Radvanyi F, Duros C, Saquet C, Blanche M, Junien C, Gourdon G (1998) Somatic instability of the CTG repeat in mice transgenic for the myotonic dystrophy region is age-dependent but not correlated to the relative intertissue transcription levels and proliferative capacities. Hum Mol Genet 7:1285–1291
Manley K, Shirley TL, Flaherty L, Messer A (1999) Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat Genet 23:471–473
Owen BA, Yang Z, Lai M, Gajek M, Badger JD, 2nd Hayes JJ, Edelmann W, Kucherlapati R, Wilson TM, McMurray CT (2005) (CAG)(n)-hairpin DNA binds to Msh2-Msh3 and changes properties of mismatch recognition. Nat Struct Mol Biol 12:663–670
Panigrahi GB, Lau R, Montgomery SE, Leonard MR, Pearson CE (2005) Slipped (CTG)*(CAG) repeats can be correctly repaired, escape repair or undergo error-prone repair. Nat Struct Mol Biol 12:654–662
Parniewski P, Staczek P (2002) Molecular mechanisms of TRS instability. Adv Exp Med Biol 516:1–25
Pearson CE, Edamura KN, Cleary JD (2005) Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet 6:729–742
Richardson LL, Pedigo C, Ann Handel M (2000) Expression of deoxyribonucleic acid repair enzymes during spermatogenesis in mice. Biol Reprod 62:789–796
Savouret C, Brisson E, Essers J, Kanaar R, Pastink A, te Riele H, Junien C, Gourdon G (2003) CTG repeat instability and size variation timing in DNA repair-deficient mice. EMBO J 22:2264–2273
Savouret C, Garcia-Cordier C, Megret J, te Riele H, Junien C, Gourdon G (2004) MSH2-dependent germinal CTG expansions are produced continuously in spermatogonia from DM1 transgenic mice. Mol Cell Biol 24:629–6637
Seznec H, Lia-Baldini A, Duros C, Fouquet C, Lacroix C, Hofmann-Radvanyi H, Junien C, Gourdon G (2000) Transgenic mice carrying large human genomic sequences with expanded CTG repeat mimic closely the DM CTG repeat intergenerational and somatic instability. Hum Mol Genet 9:1185–1194
Wheeler VC, Lebel LA, Vrbanac V, Teed A, te Riele H, MacDonald ME (2003) Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum. Hum Mol Genet 12:273–281
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) HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions. Nat Genet 23:359–362
Acknowledgements
We would like to thank Françoise Praz for providing the Msh6 monoclonal antibody and Mário Gomes-Pereira for helpful comments on the manuscript. This work was supported by grants from INSERM, the Association Française contre les Myopathies (AFM) and the Université René-Descartes Paris V. LF and CS were supported by a grant from the “Ministère Français de la Recherche et de la Technologie” and DL by a grant from AFM.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Foiry, L., Dong, L., Savouret, C. et al. Msh3 is a limiting factor in the formation of intergenerational CTG expansions in DM1 transgenic mice. Hum Genet 119, 520–526 (2006). https://doi.org/10.1007/s00439-006-0164-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-006-0164-7