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Saccharomyces cerevisiae ATM orthologue suppresses break-induced chromosome translocations

Abstract

Chromosome translocations are frequently associated with many types of blood-related cancers and childhood sarcomas. Detection of chromosome translocations assists in diagnosis, treatment and prognosis of these diseases1; however, despite their importance to such diseases, the molecular mechanisms leading to chromosome translocations are not well understood. The available evidence indicates a role for non-homologous end joining (NHEJ) of DNA double-strand breaks (DSBs) in their origin1,2,3. Here we develop a yeast-based system that induces a reciprocal chromosome translocation by formation and ligation of breaks on two different chromosomes. We show that interchromosomal end joining is efficiently suppressed by the Tel1- and Mre11–Rad50–Xrs2-dependent pathway; this is distinct from the role of Tel1 in telomeric integrity and from Mec1- and Tel1-dependent checkpoint controls. Suppression of DSB-induced chromosome translocations depends on the kinase activity of Tel1 and Dun1, and the damage-induced phosphorylation of Sae2 and histone H2AX proteins. Tel1- and Sae2-dependent tethering and promotion of 5′ to 3′ degradation of broken chromosome ends discourage error-prone NHEJ and interchromosomal NHEJ, preserving chromosome integrity on DNA damage. Our results indicate that, like human ATM, Tel1 serves as a key regulator for chromosome integrity in the pathway that reduces the risk for DSB-induced chromosome translocations, and are probably pertinent to the oncogenic chromosome translocations in ATM-deficient cells.

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Figure 1: The Tel1 pathway suppresses chromosome translocations by NHEJ.
Figure 2: Tel1- and Sae2-mediated end processing suppresses mutagenic NHEJ and chromosome translocations.
Figure 3: Tel1 and Sae2 contribute to intrachromosomal association.

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Acknowledgements

We are grateful to S. Brill, J. Haber, W. D. Heyer, M. P. Longhese, J. L. Ma, T. Paull, E-Y. Shim, P. Sung, D. Toczyski, R. Wellinger and members of the S. Lee laboratory for reagents and helpful suggestions. This work was supported by grants in the National Institutes of Health and the Texas Advanced Research program to S.E.L. S.E.L. is a Leukemia and Lymphoma Society Scholar.

Author Contributions K.L., Y.Z. and S.E.L. designed experiments. K.L. performed the chromosome translocation assay shown in Fig. 1, Supplementary Table 2 and Supplementary Figs 1–6. K.L. carried out chromatin immunoprecipitation and QAOS assays in Fig. 2. Y.Z. analysed intrachromosomal end association in Fig. 3, along with Supplementary Fig. 7. S.E.L. wrote the paper.

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Correspondence to Sang Eun Lee.

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Lee, K., Zhang, Y. & Lee, S. Saccharomyces cerevisiae ATM orthologue suppresses break-induced chromosome translocations. Nature 454, 543–546 (2008). https://doi.org/10.1038/nature07054

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