The Startling Role of Mismatch Repair in Trinucleotide Repeat Expansions

Abstract

Trinucleotide repeats are a peculiar class of microsatellites whose expansions are responsible for approximately 30 human neurological or developmental disorders. The molecular mechanisms responsible for these expansions in humans are not totally understood, but experiments in model systems such as yeast, transgenic mice, and human cells have brought evidence that the mismatch repair machinery is involved in generating these expansions. The present review summarizes, in the first part, the role of mismatch repair in detecting and fixing the DNA strand slippage occurring during microsatellite replication. In the second part, key molecular differences between normal microsatellites and those that show a bias toward expansions are extensively presented. The effect of mismatch repair mutants on microsatellite expansions is detailed in model systems, and in vitro experiments on mismatched DNA substrates are described. Finally, a model presenting the possible roles of the mismatch repair machinery in microsatellite expansions is proposed.

Prognostic and immunological role of Ras-related protein Rap1b in pan-cancer

“…The mismatch repair proteins cooperate with each other to recognize, remove and repair the mismatched bases. When the mismatch repair system is functionally abnormal, microsatellite sequences are prone to errors in the replication process, leading to mismatches, insertions, and deletions of one or more bases, leading to genomic instability and high mutant phenotypes, and increasing the risk of tumorigenesis [ 40 , 41 ]. In addition, MMR has an effect on repairing DNA replication errors in both normal and cancer cells [ 42 ], such as mutations in MMR gens that result in the occurrence of colorectal cancer.…”

Mutation and selection processes regulating short tandem repeats give rise to genetic and phenotypic diversity across species

“…This has yielded many interesting findings in recent years, motivating this review of our current understanding of these important but often overlooked genomic elements. We note that mutation and regulatory mechanisms related to pathogenic STR variants specific to humans are reviewed in detail elsewhere (Guo et al, 2017 ; Massey & Jones, 2018 ; McGinty & Mirkin, 2018 ; Mosbach et al, 2019 ; Neil et al, 2017 ; Richard, 2021 ; Wheeler & Dion, 2021 ; Xiao et al, 2022 ) and are not the primary topic of this review.…”

CORO2A is a pan-cancer prognostic biomarker and correlates with immune infiltration

“…Various MMR genes have been identi ed that rectify DNA replication errors and ensure the stability of the genome [32,33]. An aberrant MMR system increases the frequency of mismatches, insertions and other mutations in microsatellite sequences, thereby increasing the risk of genomic instability, mutant phenotypes and tumorigenesis [34,35]. Abnormal DNA hypermethylation is also common in all stages of tumor genesis and development, and overexpression of DNMT has been observed in the precancerous lesion stage.…”