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Microsatellite instability and DNA mismatch repair in human cancer
1Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Hertfordshire, UK.
Abstract:
A form of genome instability in human tumours is associated with defects in a DNA mismatch repair pathway that normally corrects replication errors. The instability is observed as highly polymorphic mono- and dinucleotide microsatellites. Alterations in microsatellite length are due to accumulated frameshift mutations that arise because of uncorrected misalignments between template and daughter DNA strands during replication. Loss of mismatch repair is associated with some familial cancers, occurs at an early stage in tumour development and confers a general mutator phenotype. The latter may accelerate the accumulation of mutations in critical target genes during progression to malignancy. Biochemical analysis is providing insights into the mechanisms of mismatch repair.
Insights
Defects in DNA mismatch repair cause genome instability in human tumors, leading to microsatellite alterations and frameshift mutations. This early-stage defect accelerates cancer progression by increasing mutation rates.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- Genome instability is a hallmark of human tumors.
- DNA mismatch repair (MMR) corrects replication errors, maintaining genomic integrity.
- Defects in MMR are linked to hereditary nonpolyposis colorectal cancer (HNPCC) and other familial cancers.
Purpose of the Study:
- To investigate the role of DNA mismatch repair defects in human tumorigenesis.
- To understand the molecular mechanisms underlying microsatellite instability.
- To explore the impact of MMR deficiency on cancer development and progression.
Main Methods:
- Analysis of microsatellite polymorphism in human tumors.
- Biochemical assays to study DNA mismatch repair pathway function.
- Investigation of mutation accumulation in MMR-deficient cells.
Main Results:
- Human tumors with MMR defects exhibit highly polymorphic mono- and dinucleotide microsatellites.
- Microsatellite length alterations result from uncorrected DNA replication misalignments and frameshift mutations.
- Loss of MMR function confers a general mutator phenotype, accelerating mutation accumulation.
Conclusions:
- DNA mismatch repair deficiency is an early event in tumorigenesis, contributing to genome instability.
- Microsatellite instability serves as a biomarker for MMR defects.
- The mutator phenotype associated with MMR loss promotes malignant progression by increasing mutations in critical genes.