Increased Hypermutation at G and C Nucleotides in Immunoglobulin Variable Genes from Mice Deficient in the MSH2 Mismatch Repair Protein

Rearranged immunoglobulin variable genes are extensively mutated after stimulation of B lymphocytes by antigen. Mutations are likely generated by an error-prone DNA polymerase, and the mismatch repair pathway may process the mispairs. To examine the role of the MSH2 mismatch repair protein in hypermutation, Msh2−/− mice were immunized with oxazolone, and B cells were analyzed for mutation in their VκOx1 light chain genes. The frequency of mutation in the repair-deficient mice was similar to that in Msh2+/+ mice, showing that MSH2-dependent mismatch repair does not cause hypermutation. However, there was a striking bias for mutations to occur at germline G and C nucleotides. The results suggest that the hypermutation pathway frequently mutates G·C pairs, and a MSH2-dependent pathway preferentially corrects mismatches at G and C.

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Role of the mismatch repair protein MSH7 in Arabidopsis adaptation to acute salt stress

Plant Physiology and Biochemistry ◽

10.1016/j.plaphy.2021.11.029 ◽

2021 ◽

Author(s):

Michelle C. Chirinos-Arias ◽

Claudia P. Spampinato

Keyword(s):

Salt Stress ◽

Mismatch Repair ◽

Repair Protein ◽

Mismatch Repair Protein

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Characterization of a rare variant (c.2635-2A>G) of the MSH2 gene in a family with Lynch syndrome

The International Journal of Biological Markers ◽

10.1177/1724600818766496 ◽

2018 ◽

Vol 33 (4) ◽

pp. 534-539 ◽

Cited By ~ 3

Author(s):

Filomena Cariola ◽

Vittoria Disciglio ◽

Anna M. Valentini ◽

Claudio Lotesoriere ◽

Candida Fasano ◽

...

Keyword(s):

Lynch Syndrome ◽

Protein Expression ◽

Mismatch Repair ◽

Splice Site ◽

Pathogenic Role ◽

Repair Protein ◽

Tumor Tissues ◽

Mismatch Repair Protein

Introduction: Lynch syndrome is caused by germline mutations in one of the mismatch repair genes ( MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Lynch syndrome is defined on the basis of clinical, pathological, and genetic findings. Accordingly, the identification of predisposing genes allows for accurate risk assessment and tailored screening protocols. Case Description: Here, we report a family case with three family members manifesting the Lynch syndrome phenotype, all of which harbor the rare variant c.2635-2A>G affecting the splice site consensus sequence of intron 15 of the MSH2 gene. This mutation was previously described only in one family with Lynch syndrome, in which mismatch repair protein expression in tumor tissues was not assessed. In this study, we report for the first time the molecular characterization of the MSH2 c.2635-2A>G variant through in silico prediction analysis, microsatellite instability, and mismatch repair protein expression experiments on tumor tissues of Lynch syndrome patients. The potential effect of the splice site variant was revealed by three splicing prediction bioinformatics tools, which suggested the generation of a new cryptic splicing site. The potential pathogenic role of this variant was also revealed by the presence of microsatellite instability and the absence of MSH2/MSH6 heterodimer protein expression in the tumor cells of cancer tissues of the affected family members. Conclusions: We provide compelling evidence in favor of the pathogenic role of the MSH2 variant c.2635-2A>G, which could induce an alteration of the canonical splice site and consequently an aberrant form of the protein product (MSH2).

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Prime Editing Efficiency and Fidelity are Enhanced in the Absence of Mismatch Repair

10.1101/2021.09.30.462548 ◽

2021 ◽

Author(s):

Joana Ferreira da Silva ◽

Goncalo Oliveira ◽

Emili Arasa-Verge ◽

Amandine Moretton ◽

Gerald Thimelthaler ◽

...

Keyword(s):

Mismatch Repair ◽

Genome Engineering ◽

Fold Increase ◽

Human Cell Lines ◽

Repair Pathway ◽

Genomic Locus ◽

Editing Efficiency ◽

Repair Protein ◽

Cellular Context ◽

Mismatch Repair Protein

Prime editing is a powerful genome engineering approach that enables the introduction of base substitutions, insertions and deletions, into any given genomic locus. But prime editing, at even the same locus, can exhibit wildly different efficiencies in various cell backgrounds. It is unclear what determines these variations in efficiencies in a given cellular context. Through a focused genetic screen targeting DNA repair factors, we show that the efficiency of prime editing is attenuated by the mismatch repair pathway. The accumulation of the mismatch repair protein MLH1 at sites of prime editing, indicates that mismatch repair acts at these regions to directly counteract the insertion of the edit. Consequently, ablation of mismatch repair yields an up to 17-fold increase in prime editing efficiency across different human cell lines, several types of edits and multiple genomic loci. Our results shed new light on the cellular requirements for prime editing and identify that ablation of mismatch repair increases editing efficiency and fidelity.

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