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Mph1p promotes gross chromosomal rearrangement through partial inhibition of homologous recombination

¹ Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892
² Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245

Correspondence to Kyungjae Myung: kmyung{at}nhgri.nih.gov

Gross chromosomal rearrangement (GCR) is a type of genomic instability associated with many cancers. In yeast, multiple pathways cooperate to suppress GCR. In a screen for genes that promote GCR, we identified MPH1, which encodes a 3'–5' DNA helicase. Overexpression of Mph1p in yeast results in decreased efficiency of homologous recombination (HR) as well as delayed Rad51p recruitment to double-strand breaks (DSBs), which suggests that Mph1p promotes GCR by partially suppressing HR. A function for Mph1p in suppression of HR is further supported by the observation that deletion of both mph1 and srs2 synergistically sensitize cells to methyl methanesulfonate-induced DNA damage. The GCR-promoting activity of Mph1p appears to depend on its interaction with replication protein A (RPA). Consistent with this observation, excess Mph1p stabilizes RPA at DSBs. Furthermore, spontaneous RPA foci at DSBs are destabilized by the mph1 mutation. Therefore, Mph1p promotes GCR formation by partially suppressing HR, likely through its interaction with RPA.

J.-Y. Hwang's present address is Cell Biology Team, Bio Technology Research Center, Korean German Institute of Technology, Mapo-Gu, 121-270 Seoul, South Korea.

A. Motegi's present address is Department of Radiation Genetics, Kyoto University Graduate School of Medicine, Yoshida Konoe, Sakyo-ku Kyoto 606-8501, Japan.

Abbreviations used in this paper: 5-FOA, 5-fluoroorotic acid; ChIP, chromatin immunoprecipitation; DSB, double-strand break; FA, Fanconi anemia; GCR, gross chromosomal rearrangement; HR, homologous recombination; MMS, methyl methanesulfonate; NHEJ, nonhomologous end joining; RPA, replication protein A; YPD, yeast extract peptone-dextrose.

© 2008 Banerjee et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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