Disease relevance of mut1

• Recent reports of premature aging in mutant mice with greatly increased rates of mitochondrial DNA mutagenesis (so-called 'mitochondrial mutator mice') appeared to confirm that accumulation of mtDNA mutations is a key mechanism of normal aging [1].
• The recombinant mouse gene (mOgg1) suppresses the mutator phenotype of mutY/mutM E. coli [2].
• It is known to be very rare in non-Hodgkin lymphomas (NHL), whereas mutator NHL is the most frequent tumor subtype in mismatch repair-deficient mice [3].
• A new mutator phenotype in breast cancer [4]?
• The observation that the MSI-H phenotype was restricted to HIV infection-related lymphomas and posttransplant lymphoproliferative disorders suggests the existence of the highly immunogenic mutator pathway as a novel oncogenic process in lymphomagenesis whose role is favored when host immunosurveillance is reduced [3].

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

• In addition, BKRF3 was able to complement an E. coli ung mutant in rifampin and nalidixic acid resistance mutator assays [10].

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

• Binding of MAb 190/4 and HAV to mut1 and mut3 cells was highly reduced, while binding to mut2 cells was not affected and binding to dog cells expressing an havcr-1 construct containing a deletion of the Cys-rich region (d1- cells) was undetectable [21].
• Mutator phenotypes in mammalian cell mutants with distinct biochemical defects and abnormal deoxyribonucleoside triphosphate pools [22].
• Moreover, while the 39 degrees C incubation gave E1 mutants a moderate spontaneous mutator phenotype, the same treatment significantly diminished the level of UV-induced 6-thioguanine resistance mutagenesis and extended the time necessary for expression of the mutation phenotype [23].
• This paper describes unusual sensitivity to bleomycin; resistance to aphidicolin, 9-beta-D-arabinofuranosyladenine, 1-beta-D-arabinofuranosylcytosine, and hydroxyurea; and a mutator phenotype as common phenotypes of two classes of previously reported mouse FM3A cell mutants with distinct biochemical defects [24].
• These results suggest that the expression of Bcr/Abl can directly induce a mutator phenotype that antedates overt neoplastic transformation, and that STI571 appears to be capable of reversing this effect [25].

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

• HAV-infected cr5 and mut2 cells but not mut1, mut3, d1-, and DR2 cells developed the characteristic cytoplasmic granular fluorescence of HAV-infected cells [21].
• This did not modify the mutator phenotype of Msh2(-/-) mice, but weakly extended survival [29].
• Thus, the mutator phenotype as a consequence of PMS2 deficiency is tissue-dependent, which may be related to the tissue-specific tumor proneness of Pms2-/- mice [30].
• Here, we report that stable siRNA-mediated silencing of Smug1 in mouse embryo fibroblasts also generates a mutator phenotype [31].
• A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1 [32].

Analytical, diagnostic and therapeutic context of mut1

• Molecular cloning of the cDNA for a mutant mouse ribonucleotide reductase M1 that produces a dominant mutator phenotype in mammalian cells [33].
• The presence of mutated p53 may confer genome instability and mutator ability, which allows cells to escape the effects of the exogenous wtp53 and contributes to the failure of wtp53 gene therapy [34].
• Because of these mutator alleles' high mutation rates, the initial treatment failure increases the probability of failures in subsequent treatments with other drugs [35].
• To determine whether the mutator activity was due to the intracellular dNTP pool imbalance, 4 dNTPs in these mutator mutants were determined by high-pressure liquid chromatography and compared to that of the wild-type cells [36].
• The size of deoxynucleoside triphosphate pool in cultured mouse FM3A cells and mutator mutants isolated from this cell line was determined by high-pressure liquid chromatography after treatment of the cells with ultraviolet light, N-methyl-N'-nitro-N-nitrosoguanidine or mitomycin C [37].

References