Increased mutagenesis and unique mutation signature associated with mitotic gene conversion.
To examine the fidelity of DNA synthesis during double-strand break (DSB) repair in Saccharomyces cerevisiae we studied gene conversion in which both strands of DNA are newly synthesized. The mutation rate increases up to 1400 times over spontaneous events, with a significantly different mutation signature. Especially prominent are microhomology-mediated template switches. Recombination-induced mutations are largely independent of mismatch repair, by DNA polymerases Polzeta, Poleta, and Pol32, but result from errors made by Poldelta and Polepsilon. These observations suggest that increased DSB frequencies in oncogene-activated mammalian cells may also increase the probability of acquiring mutations required for transition to a cancerous state.
Hicks
Wade M
WM
Department of Biology and Rosenstiel Center, Brandeis University, Waltham, MA 02454-9110, USA.
Kim
Minlee
M
Haber
James E
JE
D001483:Base Sequence; D053903:DNA Breaks, Double-Stranded; D053843:DNA Mismatch Repair; D004257:DNA Polymerase II / Q000378:metabolism; D004258:DNA Polymerase III / Q000378:metabolism; D004260:DNA Repair; D004271:DNA, Fungal / Q000096:biosynthesis; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D005785:Gene Conversion; D005800:Genes, Fungal; D008938:Mitosis; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D009857:Oncogenes; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D000099270:Y-Family DNA Polymerases
D004257:DNA Polymerase II; D004258:DNA Polymerase III; D004271:DNA, Fungal; D004259:DNA-Directed DNA Polymerase; D029701:Saccharomyces cerevisiae Proteins; C425929:DNA polymerase zeta; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases