Detection of coding microsatellite frameshift mutations in DNA mismatch repair‐deficient mouse intestinal tumors

Woerner, Stefan M.; Tosti, Elena; Yuan, Yan P.; Kloor, Matthias; Bork, Peer; Edelmann, Winfried; Gebert, Johannes

doi:10.1002/mc.22213

Cited by 34 publications

(38 citation statements)

References 43 publications

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“…We first evaluated MSI in skin tumors from K14ΔNLef1 mice and K14ΔNLef1:cKO mice. We analyzed the relative allele frequency of five microsatellite regions, as previously described (Woerner et al , ; Germano et al , ; Keysselt et al , ). Three markers (Bat64, AA003063, and L24372) showed a shift in allele distribution, two of which were significant (Fig C).…”

Section: Resultsmentioning

confidence: 99%

Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

et al. 2019

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Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a β‐catenin‐independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9‐positive Lef1‐negative hair follicle progenitors that give rise to the upper SG. Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer.

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Section: Resultsmentioning

confidence: 99%

Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

et al. 2019

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“…In addition, the frameshifts are not assumed to be tolerated in the sense that they are not changed. However, if they are not removed immediately by selecting against but could be preserved in the evolutionary history, they are assumed to be repairable [116][117][118][119][120]. At present, we are investigating the mechanism of how a frameshift mutation is repaired [121].…”

Section: Discussionmentioning

confidence: 99%

Frameshift and wild-type proteins are highly similar because the genetic code and genomes were optimized for frameshift tolerance

Wang

Dong

Chen

et al. 2016

Preprint

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Frameshift mutation yields truncated, dysfunctional product proteins, leading to loss-of-function, genetic disorders or even death. Frameshift mutations have been considered as mostly harmful and of little importance for the molecular evolution of proteins. Frameshift protein sequences, encoded by the alternative reading frames of a coding gene, have been therefore considered as meaningless. However, existing studies had shown that frameshift genes/proteins are widely existing and sometimes functional. It is puzzling how a frameshift kept its structure and functionality while its amino-acid sequence is changed substantially. Here we demonstrate that the protein sequences of the frameshifts are highly conservative when compared with the wild-type protein sequence, and the similarities among the three protein sequences encoded in the three reading frames of a coding gene are defined mainly by the genetic code. In the standard genetic code, amino acid substitutions assigned to frameshift codon substitutions are far more conservative than those assigned to random substitutions. The frameshift tolerability of the standard genetic code ranks in the top 1.0-5.0% of all possible genetic codes, showing that the genetic code is optimal in terms of frameshift tolerance. In some higher species, the shiftability is further optimized at gene- or genome-level by a biased usage of codons and codon pairs, in which frameshift-tolerable codons/codon pairs are overrepresented in their genomes.

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“…MSI analysis was performed as in Woerner et al (14). MSI was determined by comparing DNA fragment analysis of mononucleotide markers in tumors relative to tail DNA from the same mouse.…”

Section: Methodsmentioning

confidence: 99%

Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis

et al. 2017

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Aberrant silencing of genes by DNA methylation contributes to cancer, yet how this process is initiated remains unclear. Using a murine model of inflammation-induced tumorigenesis, we tested the hypothesis that inflammation promotes recruitment of epigenetic proteins to chromatin, initiating methylation and gene silencing in tumors. Compared to normal epithelium and non-inflammation-induced tumors, inflammation-induced tumors gained DNA methylation at CpG islands, some of which are associated with putative tumor suppressor genes. Hypermethylated genes exhibited enrichment of repressive chromatin marks and reduced expression prior to tumorigenesis, at a time point coinciding with peak levels of inflammation-associated DNA damage. Loss of MutS homolog 2 (MSH2), a mismatch repair (MMR) protein, abrogated early inflammation-induced epigenetic alterations and DNA hypermethylation alterations observed in inflammation-induced tumors. These results indicate that early epigenetic alterations initiated by inflammation and MMR proteins lead to gene silencing during tumorigenesis, revealing a novel mechanism of epigenetic alterations in inflammation-driven cancer. Understanding such mechanisms will inform development of pharmacotherapies to reduce carcinogenesis.

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Detection of coding microsatellite frameshift mutations in DNA mismatch repair‐deficient mouse intestinal tumors

Cited by 34 publications

References 43 publications

Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

Frameshift and wild-type proteins are highly similar because the genetic code and genomes were optimized for frameshift tolerance

Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis

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