ArticleProceedings of the National Academy of Sciences of the United States of America1999
Different mutator phenotypes in Mlh1- versus Pms2-deficient mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 136 citations in OpenAlex.
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- All three MutL complexes are required for repeat expansion in a human stem cell model of CAG-repeat expansion mediated glutaminase deficiency.Scientific reports · 2024Article
- All three MutL complexes are required for repeat expansion in a human stem cell model of CAG-repeat expansion mediated glutaminase deficiency.bioRxiv : the preprint server for biology · 2024Article
- Genetically engineered mouse models for hereditary cancer syndromes.Cancer science · 2023Review
- A calibrated cell-based functional assay to aid classification of MLH1 DNA mismatch repair gene variants.Human mutation · 2022Article
- Spectrum of DNA mismatch repair failures viewed through the lens of cancer genomics and implications for therapy.Clinical science (London, England : 1979) · 2022Article
- A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing.Cell death & disease · 2021Article
- Mutational signatures of DNA mismatch repair deficiency inGenome research · 2018Article
- The mutational profile and infiltration pattern of murine MLH1-/- tumors: concurrences, disparities and cell line establishment for functional analysis.Oncotarget · 2016Article
- An intact Pms2 ATPase domain is not essential for male fertility.DNA repair · 2016Article
- Chlorinated Water Modulates the Development of Colorectal Tumors with Chromosomal Instability and Gut Microbiota in Apc-Deficient Mice.PloS one · 2015Article
- Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach.Human genomics · 2013Article
- A systems approach defining constraints of the genome architecture on lineage selection and evolvability during somatic cancer evolution.Biology open · 2013Article
- Mismatch repair deficiency: a temozolomide resistance factor in medulloblastoma cell lines that is uncommon in primary medulloblastoma tumours.British journal of cancer · 2012Article
- Article
- Conservation of functional asymmetry in the mammalian MutLα ATPase.DNA repair · 2010Article
- Msh6 protects mature B cells from lymphoma by preserving genomic stability.The American journal of pathology · 2010Article
- The Mutyh base excision repair gene influences the inflammatory response in a mouse model of ulcerative colitis.PloS one · 2010Article
- PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- Microsatellite instability in colorectal cancer.Gastroenterology · 2010Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Deficiencies in DNA mismatch repair (MMR) result in increased mutation rates and cancer risk in both humans and mice. Mouse strains homozygous for knockouts of either the Pms2 or Mlh1 MMR gene develop cancer but exhibit very different tumor spectra; only Mlh1(-/-) animals develop intestinal tumors. We carried out a detailed study of the microsatellite mutation spectra in each knockout strain. Five mononucleotide repeat tracts at four different chromosomal locations were studied by using single-molecule PCR or an in vivo forward mutation assay. Three dinucleotide repeat loci also were examined. Surprisingly, the mononucleotide repeat mutation frequency in Mlh1(-/-) mice was 2- to 3-fold higher than in Pms2(-/-) animals. The higher mutation frequency in Mlh1(-/-) mice may be a consequence of some residual DNA repair capacity in the Pms2(-/-) animals. Relevant to this idea, we observed that Pms2(-/-) mice exhibit almost normal levels of Mlh1p, whereas Mlh1(-/-) animals lack both Mlh1p and Pms2p. Comparison between Mlh1(-/-) animals and Mlh1(-/-) and Pms2(-/-) double knockout mice revealed little difference in mutator phenotype, suggesting that Mlh1 nullizygosity is sufficient to inactivate MMR completely. The findings may provide a basis for understanding the greater predisposition to intestinal cancer of Mlh1(-/-) mice. Small differences (2- to 3-fold) in mononucleotide repeat mutation rates may have dramatic effects on tumor development, requiring multiple genetic alterations in coding regions. Alternatively, this strain difference in tumor spectra also may be related to the consequences of the absence of Pms2p compared with the absence of both Pms2p and Mlh1p on as yet little understood cellular processes.
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