Frameshift mutator mutations

• Published in: Nature (London) Vol. 382; no. 6591; pp. 499 - 500
• Main Authors: Malkhosyan, Sergei, Rampino, Nicholas, Yamamoto, Hiroyuki, Perucho, Manuel
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 08.08.1996
• Subjects: Base Sequence; DNA Primers; DNA Repair; DNA-Binding Proteins - genetics; Frameshift Mutation; Humans; Microsatellite Repeats; Molecular Sequence Data; Multidrug Resistance-Associated Proteins; MutS Homolog 3 Protein; Neoplasms - genetics; Polymerase Chain Reaction; Proteins - genetics; Tumor Cells, Cultured
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/382499a0

Human tumour cells of the microsatellite mutator phenotype (MMP) accumulate many thousands of somatic mutations in simple, repeated nucleotide sequences. The MMP is a landmark of hereditary non-polyposis colorectal cancer (HNPCC) and a significant fraction of other sporadic tumours of the gastrointestinal and urogenital tracts. MMP tumours exhibit a low frequency of mutations in the p53 tumour-suppressor gene. In contrast, inactivation of the type II transforming growth factor- beta receptor in gastrointestinal cancer of the MMP commonly occurs by frameshifts in a poly(A) nucleotide track in the gene's coding region. Human tumours of the MMP have been associated with defects in the human homologues (hMSH2 and hMLH1) of the Escherichia coli MutS and MutL families of DNA mismatch-repair genes, respectively; hMSH3 (also called DUG) and hMSH6 (also called GTBP) are two other MutS genes. The functions of DNA mismatch recognition and repair enzymatic complexes in humans are poorly understood. In the yeast Saccharomyces cerevisiae, MSH3 and MSH6 are part of the MSH2-dependent repair pathway, contributing to the stabilization of microsatellite sequences. We have found that tracks of 8 deoxyadenosines and 8 deoxycytosines present in the coding regions of hMSH3 (codons 381-383) and hMSH6 (codons 1,116-1,118), respectively, are hotspots for frameshift mutations in MMP tumours.