Hypermutability of homonucleotide runs in mismatch repair and DNA polymerase proofreading yeast mutants.
Homonucleotide runs in coding sequences are hot spots for frameshift mutations and potential sources of genetic changes leading to cancer in humans having a mismatch repair defect. We examined frameshift mutations in homonucleotide runs of deoxyadenosines ranging from 4 to 14 bases at the same position in the LYS2 gene of the yeast Saccharomyces cerevisiae. In the msh2 mismatch repair mutant, runs of 9 to 14 deoxyadenosines are 1,700-fold to 51,000-fold, respectively, more mutable for single-nucleotide deletions than are runs of 4 deoxyadenosines. These frameshift mutations can account for up to 99% of all forward mutations inactivating the 4-kb LYS2 gene. Based on results with single and double mutations of the POL2 and MSH2 genes, both DNA polymerase epsilon proofreading and mismatch repair are efficient for short runs while only the mismatch repair system prevents frameshift mutations in runs of > or = 8 nucleotides. Therefore, coding sequences containing long homonucleotide runs are likely to be at risk for mutational inactivation in cells lacking mismatch repair capability.
Tran
H T
HT
Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Keen
J D
JD
Kricker
M
M
Resnick
M A
MA
Gordenin
D A
DA
D001483:Base Sequence; D004257:DNA Polymerase II / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D004271:DNA, Fungal / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D003839:Deoxyadenosines / Q000378:metabolism; D016368:Frameshift Mutation; D005656:Fungal Proteins; D006801:Humans; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein; D016296:Mutagenesis; D009692:Nucleic Acid Heteroduplexes / Q000235:genetics*; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins
D004271:DNA, Fungal; D004268:DNA-Binding Proteins; D003839:Deoxyadenosines; D005656:Fungal Proteins; D009692:Nucleic Acid Heteroduplexes; D029701:Saccharomyces cerevisiae Proteins; D004257:DNA Polymerase II; D004259:DNA-Directed DNA Polymerase; C489751:MSH2 protein, S cerevisiae; D051718:MutS Homolog 2 Protein