Hypermutability of homonucleotide runs in mismatch repair and DNA polymerase proofreading yeast mutants
HT Tran, JD Keen, M Kricker, MA Resnick… - … and cellular biology, 1997 - Am Soc Microbiol
HT Tran, JD Keen, M Kricker, MA Resnick, DA Gordenin
Molecular and cellular biology, 1997•Am Soc MicrobiolHomonucleotide 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 …
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 …
Abstract
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 ɛ proofreading and mismatch repair are efficient for short runs while only the mismatch repair system prevents frameshift mutations in runs of≥ 8 nucleotides. Therefore, coding sequences containing long homonucleotide runs are likely to be at risk for mutational inactivation in cells lacking mismatch repair capability.
American Society for Microbiology