Specific pathways prevent duplication-mediated genome rearrangements

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Abstract

We have investigated the ability of different regions of the left arm of Saccharomyces cerevisiae chromosome V to participate in the formation of gross chromosomal rearrangements (GCRs). We found that the 4.2-kilobase HXT13-DSF1 region sharing divergent homology with chromosomes IV, X and XIV, similar to mammalian segmental duplications, was ‘at risk’ for participating in duplication-mediated GCRs generated by homologous recombination. Numerous genes and pathways, including SGS1, TOP3, RMI1, SRS2, RAD6, SLX1, SLX4, SLX5, MSH2, MSH6, RAD10 and the DNA replication stress checkpoint requiring MRC1 and TOF1, were highly specific for suppressing these GCRs compared to GCRs mediated by single-copy sequences. These results indicate that the mechanisms for formation and suppression of rearrangements occurring in regions containing at-risk sequences differ from those occurring in regions of single-copy sequence. This explains how extensive genome instability is prevented in eukaryotic cells whose genomes contain numerous divergent repeated sequences.

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Figure 1: New assays for evaluating the genes that suppress the accumulation of GCRs.
Figure 2: Summary of the types of GCRs detected in the HXT13-DSF1 -region-mediated GCR assay.

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ArrayExpress

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Microarray data have been submitted to ArrayExpress (http://www.ebi.ac.uk/arrayexpress) with accession number E-TABM-714.

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Acknowledgements

We thank the UCSD Microarray Core Facility for assistance in the aCGH experiments and C. Smith, S. Shell and J. Petrini for comments on the manuscript. This work was supported by NIH grant GM26017.

Author Contributions C.D.P., R.D.K. and T.K.H. designed the experiments. C.D.P. and T.K.H. performed the experiment. C.D.P. and R.D.K. analysed the data and wrote the manuscript.

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Correspondence to Richard D. Kolodner.

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Putnam, C., Hayes, T. & Kolodner, R. Specific pathways prevent duplication-mediated genome rearrangements. Nature 460, 984–989 (2009) doi:10.1038/nature08217

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