Tissue-specific reduction in MLH1 expression induces microsatellite instability in intestine of Mlh1+/- mice

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Abstract

Tumors of Lynch syndrome (LS) patients display high levels of microsatellite instability (MSI), which results from complete loss of DNA mismatch repair (MMR), in line with Knudson’s two-hit hypothesis. Why some organs, in particular those of the gastrointestinal (GI) tract, are prone to tumorigenesis in LS remains unknown. We hypothesized that MMR is haploinsufficient in certain tissues, compromising microsatellite stability in a tissue-specific manner before tumorigenesis. Using mouse genetics, we tested how levels of MLH1, a central MMR protein, affect age- and tissue-specific microsatellite stability in vivo and whether elevated MSI is detectable prior to loss of MMR function and to neoplastic growth.

To assess putative tissue-specific MMR haploinsufficiency, we determined relevant molecular phenotypes (MSI, Mlh1 promoter methylation status, MLH1 protein and RNA levels) in jejuna of Mlh1+/− mice and compared them to those in spleen, as well as to MMR-proficient and -deficient controls (Mlh1+/+ and Mlh1−/− mice). While spleen MLH1 levels of Mlh1+/− mice were, as expected, approximately 50 % compared to wildtype mice, MLH1 levels in jejunum varied substantially between individual Mlh1+/− mice and moreover, decreased with age. Mlh1+/− mice with soma-wide Mlh1 promoter methylation often displayed severe MLH1 depletion in jejunum. Reduced (but still detectable) MLH1 levels correlated with elevated MSI in Mlh1+/− jejunum. MSI in jejunum increased with age, while in spleens of the same mice, MLH1 levels and microsatellites remained stable. Thus, MLH1 expression levels are particularly labile in intestine of Mlh1+/− mice, giving rise to tissue-specific MSI long before neoplasia. A similar mechanism likely also operates also in the human GI epithelium and could explain the wide range in age-of-onset of LS-associated tumorigenesis.
Original languageEnglish
Article number103178
JournalDNA Repair
Volume106
Number of pages10
ISSN1568-7864
DOIs
Publication statusPublished - Oct 2021
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 1184 Genetics, developmental biology, physiology
  • Lynch syndrome
  • Mlh1 haploinsufficiency
  • Microsatellite instability
  • Mlh1 promoter methylation
  • MISMATCH REPAIR
  • REPEAT MARKERS
  • TARGET GENES
  • MUTATIONS
  • MSH2
  • DNA
  • CANCER
  • HYPERMETHYLATION
  • PATHOGENESIS
  • EPIMUTATION

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