Frameshift mutagenesis and microsatellite instability induced by human alkyladenine DNA glycosylase.

Abstract

Human alkyladenine DNA glycosylase (hAAG) excises alkylated purines, hypoxanthine, and etheno bases from DNA to form abasic (AP) sites. Surprisingly, elevated expression of hAAG increases spontaneous frameshift mutagenesis. By random mutagenesis of eight active site residues, we isolated hAAG-Y127I/H136L double mutant that induces even higher rates of frameshift mutation than does the wild-type hAAG; the Y127I mutation accounts for the majority of the hAAG-Y127I/H136L-induced mutator phenotype. The hAAG-Y127I/H136L and hAAG-Y127I mutants increased the rate of spontaneous frameshifts by up to 120-fold in S. cerevisiae and also induced high rates of microsatellite instability (MSI) in human cells. hAAG and its mutants bind DNA containing one and two base-pair loops with significant affinity, thus shielding them from mismatch repair; the strength of such binding correlates with their ability to induce the mutator phenotype. This study provides important insights into the mechanism of hAAG-induced genomic instability.

• Authors: Joanna Klapacz, Gondichatnahalli M Lingaraju, Haiwei H Guo, Dharini Shah, Ayelet Moar-Shoshani, Lawrence A Loeb, Leona D Samson
• Journal: Molecular cell (Mol Cell) Vol. 37 Issue 6 Pg. 843-53 (Mar 26 2010) ISSN: 1097-4164 [Electronic] United States
• PMID: 20347426 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: (c) 2010 Elsevier Inc. All rights reserved.

Chemical References

• Saccharomyces cerevisiae Proteins
• 3-methyladenine-DNA glycosylase
• DNA Glycosylases
• MAG1 protein, S cerevisiae

Topics

• Catalytic Domain
• DNA Glycosylases (chemistry, genetics, metabolism)
• DNA Mismatch Repair
• Frameshift Mutation
• Gene Expression Regulation, Enzymologic
• Humans
• K562 Cells
• Microsatellite Instability
• Models, Molecular
• Phenotype
• Saccharomyces cerevisiae (genetics, metabolism)
• Saccharomyces cerevisiae Proteins (genetics, metabolism)