This proposal focuses on several mutational changes accompanying DNA repair in budding yeast. DNA repair is induced by galactose-regulated expression of the site-specific HO endonuclease, creating a single double-strand break (DSB). One major goal is to understand complex mutations associated by template switching that occur during gene conversion. Two types of repair will be studied: 1. Quasipalindrome mutation formation during gene conversion and 2. Interchromosomal microhomology-mediated template switching during gene conversion. Genetic analysis of helicases and other repair factors will be screened to find proteins that control the level of these two events, along with an exploration of the role of chromatin. A second goal is to understand changes in repeat copy number during gene conversion, motivated by our recent discovery of important differences between DSB break repair and gap repair. In collaboration with Mitch McVey, another member of this Program Project who focuses on DSB repair in fruit flies, we will assess the frequency of abortive gap repair leading to deletions between repeated sequences within the copied region.
Mutations associated with repair of chromosomal breaks are an important factor in the origin of human disease. Our recent work has also shed new light on the origin of quasipalindrome mutations. Most surprising was our finding that three types of mutations characterized as template switches (frameshifts, quasipalindromes and interchromosomal homeologous recombination events) all were driven by the wild type DNA polymerase 5. Further characterization of these types of events and the proteins that normally prevent their appearance is a fundamentally important goal in understanding the origin of mutations affecting human health and disease.
|Beagan, Kelly; McVey, Mitch (2016) Linking DNA polymerase theta structure and function in health and disease. Cell Mol Life Sci 73:603-15|
|Rodgers, Kasey; McVey, Mitch (2016) Error-Prone Repair of DNA Double-Strand Breaks. J Cell Physiol 231:15-24|
|Aksenova, Anna Y; Han, Gil; Shishkin, Alexander A et al. (2015) Expansion of Interstitial Telomeric Sequences in Yeast. Cell Rep 13:1545-51|
|Shah, Kartik A; Mirkin, Sergei M (2015) The hidden side of unstable DNA repeats: Mutagenesis at a distance. DNA Repair (Amst) 32:106-12|
|Kloosterman, Wigard P; Francioli, Laurent C; Hormozdiari, Fereydoun et al. (2015) Characteristics of de novo structural changes in the human genome. Genome Res 25:792-801|
|Haber, James E (2015) TOPping off meiosis. Mol Cell 57:577-81|
|Usdin, Karen; House, Nealia C M; Freudenreich, Catherine H (2015) Repeat instability during DNA repair: Insights from model systems. Crit Rev Biochem Mol Biol 50:142-67|
|Pandey, Shristi; Ogloblina, Anna M; Belotserkovskii, Boris P et al. (2015) Transcription blockage by stable H-DNA analogs in vitro. Nucleic Acids Res 43:6994-7004|
|Su, Xiaofeng A; Dion, Vincent; Gasser, Susan M et al. (2015) Regulation of recombination at yeast nuclear pores controls repair and triplet repeat stability. Genes Dev 29:1006-17|
|House, Nealia C M; Yang, Jiahui H; Walsh, Stephen C et al. (2014) NuA4 initiates dynamic histone H4 acetylation to promote high-fidelity sister chromatid recombination at postreplication gaps. Mol Cell 55:818-28|
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