1. Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA

Correspondence to: Sang Eun Lee¹ Correspondence and requests for materials should be addressed to S.E.L. (Email: lees4@uthscsa.edu).

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 origin^{1, 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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