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Gene Review

mut1  -  mutator 1

Mus musculus

Synonyms: mut-1
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Disease relevance of mut1


High impact information on mut1

  • Although we observed an 11-fold increase in mitochondrial point mutations with age, we report that a mitochondrial mutator mouse was able to sustain a 500-fold higher mutation burden than normal mice, without any obvious features of rapidly accelerated aging [5].
  • The mutator hypothesis of tumorigenesis suggests that loss of chromosomal stability or maintenance functions results in elevated mutation rates, leading to the accumulation of the numerous mutations required for multistep carcinogenesis [6].
  • Msh2-deficient cells have lost mismatch binding and have acquired microsatellite instability, a mutator phenotype, and tolerance to methylating agents [7].
  • Microsatellite (MS) mutations can potentially unravel the past of mutator phenotype tumors, with greater genetic diversity expected in older regions [8].
  • Microsatellite instability: the mutator that mutates the other mutator [9].

Chemical compound and disease context of mut1


Biological context of mut1

  • Our data indicate that although the TCR transgene is expressed in B cells, it is not efficiently targeted by the mutator mechanism [11].
  • Somatic hypermutation of Ig genes is probably dependent on transcription of the target gene via a mutator factor associated with the RNA polymerase (Storb, U., E.L. Klotz, J. Hackett, Jr., K. Kage, G. Bozek, and T.E. Martin. 1998. J. Exp. Med. 188:689-698) [12].
  • The data favor a model of somatic hypermutation where the fine specificity of the mutations is determined by nucleotide sequence preferences of a mutator factor, and where the general site of mutagenesis is determined by the pausing of the RNA polymerase due to secondary structures within the nascent RNA [13].
  • Mutation pattern of immunoglobulin transgenes is compatible with a model of somatic hypermutation in which targeting of the mutator is linked to the direction of DNA replication [14].
  • The Bcl-2 gene therefore combines two separable cancer-prone phenotypes: apoptosis repression and a genetic instability/mutator phenotype [15].

Anatomical context of mut1

  • These mutants also exhibit high frequencies of Tc1 germ-line transposition, and this results in a mutator phenotype [16].
  • Additionally, MMR-deficient cell lines display a mutator phenotype and resistance to several cytotoxic agents, including compounds widely used in cancer chemotherapy [17].
  • We conclude that the participation of CD4+ helper cells is required for full activation of the mutator in GC and takes place in a dose-dependent fashion [18].
  • Precursor cells from bone marrow appear to contain the enzyme terminal deoxyribonucleotidyl transferase (Tdt), an agent suggested as a potential somatic mutator [19].
  • We propose that expansion of the stem cell compartment and induction of a mutator phenotype are relevant features underlying the leukemic potential of AML-associated fusion proteins [20].

Associations of mut1 with chemical compounds


Regulatory relationships of mut1

  • We report here the lack of a mutator phenotype for inactivating autosomal mutations in solid tissues of the Atm-deficient mice [26].
  • We next compared this mutability preference with those in hypermutating Ramos cells and in msh2(-/-)ung(-/-) mice, since both are reduced or deficient in UNG- and/or Msh2-induced mutations and are thus likely to reflect the sequence specificity of the mutator in vivo [27].
  • Mutator phenotype of BCR--ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase beta [28].

Other interactions of mut1


Analytical, diagnostic and therapeutic context of mut1


  1. Mitochondrial DNA mutations and aging: a case closed? Khrapko, K., Vijg, J. Nat. Genet. (2007) [Pubmed]
  2. Cloning and characterization of a mammalian 8-oxoguanine DNA glycosylase. Rosenquist, T.A., Zharkov, D.O., Grollman, A.P. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  3. The mutator pathway is a feature of immunodeficiency-related lymphomas. Duval, A., Raphael, M., Brennetot, C., Poirel, H., Buhard, O., Aubry, A., Martin, A., Krimi, A., Leblond, V., Gabarre, J., Davi, F., Charlotte, F., Berger, F., Gaidano, G., Capello, D., Canioni, D., Bordessoule, D., Feuillard, J., Gaulard, P., Delfau, M.H., Ferlicot, S., Eclache, V., Prevot, S., Guettier, C., Lefevre, P.C., Adotti, F., Hamelin, R. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  4. A new mutator phenotype in breast cancer? de Boer, J.G. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  5. Mitochondrial point mutations do not limit the natural lifespan of mice. Vermulst, M., Bielas, J.H., Kujoth, G.C., Ladiges, W.C., Rabinovitch, P.S., Prolla, T.A., Loeb, L.A. Nat. Genet. (2007) [Pubmed]
  6. Female embryonic lethality in mice nullizygous for both Msh2 and p53. Cranston, A., Bocker, T., Reitmair, A., Palazzo, J., Wilson, T., Mak, T., Fishel, R. Nat. Genet. (1997) [Pubmed]
  7. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. de Wind, N., Dekker, M., Berns, A., Radman, M., te Riele, H. Cell (1995) [Pubmed]
  8. Somatic microsatellite mutations as molecular tumor clocks. Shibata, D., Navidi, W., Salovaara, R., Li, Z.H., Aaltonen, L.A. Nat. Med. (1996) [Pubmed]
  9. Microsatellite instability: the mutator that mutates the other mutator. Perucho, M. Nat. Med. (1996) [Pubmed]
  10. Characterization of the uracil-DNA glycosylase activity of Epstein-Barr virus BKRF3 and its role in lytic viral DNA replication. Lu, C.C., Huang, H.T., Wang, J.T., Slupphaug, G., Li, T.K., Wu, M.C., Chen, Y.C., Lee, C.P., Chen, M.R. J. Virol. (2007) [Pubmed]
  11. Analysis of a T cell receptor gene as a target of the somatic hypermutation mechanism. Hackett, J., Stebbins, C., Rogerson, B., Davis, M.M., Storb, U. J. Exp. Med. (1992) [Pubmed]
  12. Different mismatch repair deficiencies all have the same effects on somatic hypermutation: intact primary mechanism accompanied by secondary modifications. Kim, N., Bozek, G., Lo, J.C., Storb, U. J. Exp. Med. (1999) [Pubmed]
  13. A hypermutable insert in an immunoglobulin transgene contains hotspots of somatic mutation and sequences predicting highly stable structures in the RNA transcript. Storb, U., Klotz, E.L., Hackett, J., Kage, K., Bozek, G., Martin, T.E. J. Exp. Med. (1998) [Pubmed]
  14. Mutation pattern of immunoglobulin transgenes is compatible with a model of somatic hypermutation in which targeting of the mutator is linked to the direction of DNA replication. Rogerson, B., Hackett, J., Peters, A., Haasch, D., Storb, U. EMBO J. (1991) [Pubmed]
  15. A novel role for the Bcl-2 protein family: specific suppression of the RAD51 recombination pathway. Saintigny, Y., Dumay, A., Lambert, S., Lopez, B.S. EMBO J. (2001) [Pubmed]
  16. Activation of a transposable element in the germ line but not the soma of Caenorhabditis elegans. Collins, J., Saari, B., Anderson, P. Nature (1987) [Pubmed]
  17. DNA mismatch repair and cancer. Prolla, T.A. Curr. Opin. Cell Biol. (1998) [Pubmed]
  18. Facultative role of germinal centers and T cells in the somatic diversification of IgVH genes. Miller, C., Stedra, J., Kelsoe, G., Cerny, J. J. Exp. Med. (1995) [Pubmed]
  19. Hematopoietic thymocyte precursors: IV. Enrichment of the precursors and evidence for heterogeneity. Basch, R.S., Kadish, J.L., Goldstein, G. J. Exp. Med. (1978) [Pubmed]
  20. Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair. Alcalay, M., Meani, N., Gelmetti, V., Fantozzi, A., Fagioli, M., Orleth, A., Riganelli, D., Sebastiani, C., Cappelli, E., Casciari, C., Sciurpi, M.T., Mariano, A.R., Minardi, S.P., Luzi, L., Muller, H., Di Fiore, P.P., Frosina, G., Pelicci, P.G. J. Clin. Invest. (2003) [Pubmed]
  21. The Cys-rich region of hepatitis A virus cellular receptor 1 is required for binding of hepatitis A virus and protective monoclonal antibody 190/4. Thompson, P., Lu, J., Kaplan, G.G. J. Virol. (1998) [Pubmed]
  22. Mutator phenotypes in mammalian cell mutants with distinct biochemical defects and abnormal deoxyribonucleoside triphosphate pools. Weinberg, G., Ullman, B., Martin, D.W. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  23. Incubation at the nonpermissive temperature induces deficiencies in UV resistance and mutagenesis in mouse mutant cells expressing a temperature-sensitive ubiquitin-activating enzyme (E1). Ikehata, H., Kaneda, S., Yamao, F., Seno, T., Ono, T., Hanaoka, F. Mol. Cell. Biol. (1997) [Pubmed]
  24. Unusual sensitivity to bleomycin and joint resistance to 9-beta-D-arabinofuranosyladenine and 1-beta-D-arabinofuranosylcytosine of mouse FM3A cell mutants with altered ribonucleotide reductase and thymidylate synthase. Ayusawa, D., Iwata, K., Seno, T. Cancer Res. (1983) [Pubmed]
  25. Measurement of genomic instability in preleukemic P190BCR/ABL transgenic mice using inter-simple sequence repeat polymerase chain reaction. Brain, J.M., Goodyer, N., Laneuville, P. Cancer Res. (2003) [Pubmed]
  26. Solid tissues removed from ATM homozygous deficient mice do not exhibit a mutator phenotype for second-step autosomal mutations. Turker, M.S., Gage, B.M., Rose, J.A., Ponomareva, O.N., Tischfield, J.A., Stambrook, P.J., Barlow, C., Wynshaw-Boris, A. Cancer Res. (1999) [Pubmed]
  27. The mutation spectrum of purified AID is similar to the mutability index in Ramos cells and in ung(-/-)msh2(-/-) mice. Larijani, M., Frieder, D., Basit, W., Martin, A. Immunogenetics (2005) [Pubmed]
  28. Mutator phenotype of BCR--ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase beta. Canitrot, Y., Lautier, D., Laurent, G., Fréchet, M., Ahmed, A., Turhan, A.G., Salles, B., Cazaux, C., Hoffmann, J.S. Oncogene (1999) [Pubmed]
  29. Suppression of intestinal and mammary neoplasia by lifetime administration of aspirin in Apc(Min/+) and Apc(Min/+), Msh2(-/-) mice. Sansom, O.J., Stark, L.A., Dunlop, M.G., Clarke, A.R. Cancer Res. (2001) [Pubmed]
  30. Loss of heterozygosity and point mutation at Aprt locus in T cells and fibroblasts of Pms2-/- mice. Shao, C., Yin, M., Deng, L., Stambrook, P.J., Doetschman, T., Tischfield, J.A. Oncogene (2002) [Pubmed]
  31. C --> T mutagenesis and gamma-radiation sensitivity due to deficiency in the Smug1 and Ung DNA glycosylases. An, Q., Robins, P., Lindahl, T., Barnes, D.E. EMBO J. (2005) [Pubmed]
  32. A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1. Garza, R., Hudson, R.A., McMahan, C.A., Walter, C.A., Vogel, K.S. Mutat. Res. (2007) [Pubmed]
  33. Molecular cloning of the cDNA for a mutant mouse ribonucleotide reductase M1 that produces a dominant mutator phenotype in mammalian cells. Caras, I.W., Martin, D.W. Mol. Cell. Biol. (1988) [Pubmed]
  34. Failure of wild-type p53 gene therapy in human cancer cells expressing a mutant p53 protein. Vinyals, A., Peinado, M.A., Gonzalez-Garrigues, M., Monzó, M., Bonfil, R.D., Fabra, A. Gene Ther. (1999) [Pubmed]
  35. Mutator bacteria as a risk factor in treatment of infectious diseases. Giraud, A., Matic, I., Radman, M., Fons, M., Taddei, F. Antimicrob. Agents Chemother. (2002) [Pubmed]
  36. Isolation and characterization of mutator mutants from cultured mouse FM3A cells. Hyodo, M., Ito, N., Koyama, H., Suzuki, K. Mutat. Res. (1984) [Pubmed]
  37. Deoxynucleoside triphosphate pool of mouse FM3A cell lines unaffected by mutagen treatment. Hyodo, M., Ito, N., Suzuki, K. Biochem. Biophys. Res. Commun. (1984) [Pubmed]
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