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Gross chromosomal rearrangements in Saccharomyces cerevisiae replication and recombination defective mutants

Nature Genetics volume 23, pages 81–85 (1999)Cite this article

Abstract

Cancer progression is often associated with the accumulation of gross chromosomal rearrangements (GCRs), such as translocations, deletion of a chromosome arm, interstitial deletions or inversions1,2,3. In many instances, GCRs inactivate tumour-suppressor genes or generate novel fusion proteins that initiate carcinogenesis3,4. The mechanism underlying GCR formation appears to involve interactions between DNA sequences of little or no homology5,6,7,8. We previously demonstrated that mutations in the gene encoding the largest subunit of the Saccharomyces cerevisiae single-stranded DNA binding protein (RFA1) increase microhomology-mediated GCR formation8. To further our understanding of GCR formation, we have developed a novel mutator assay in S. cerevisiae that allows specific detection of such events. In this assay, the rate of GCR formation was increased 600–5,000-fold by mutations in RFA1, RAD27, MRE11, XRS2 and RAD50, but was minimally affected by mutations in RAD51, RAD54, RAD57, YKU70, YKU80, LIG4 and POL30. Genetic analysis of these mutants suggested that at least three distinct pathways can suppress GCRs: two that suppress microhomology-mediated GCRs (RFA1 and RAD27) and one that suppresses non-homology–mediated GCRs (RAD50/MRE11/XRS2).

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Figure 1: Assay for gross chromosomal rearrangements.
Figure 2: Proposed mechanisms for generation and suppression of GCRs.

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Acknowledgements

We thank T. Nakagawa, K.J. Myung and A. Datta for discussions and comments, and J. Weger and J. Green for performing DNA sequencing. This work was supported by NIH grants GM26017 and GM50006 to R.D.K.

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  1. Cancer Center and Department of Medicine, Ludwig Institute for Cancer Research, University of California-San Diego School of Medicine, La Jolla, 92093, California, USA

    Clark Chen & Richard D. Kolodner

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Correspondence to Richard D. Kolodner.

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Chen, C., Kolodner, R. Gross chromosomal rearrangements in Saccharomyces cerevisiae replication and recombination defective mutants. Nat Genet 23, 81–85 (1999). https://doi.org/10.1038/12687

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