MCB Accepts, published online ahead of print on 16 July 2007

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Mol. Cell. Biol. doi:10.1128/MCB.00471-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mdt1 facilitates efficient repair of blocked DNA double-strand breaks and recombinational maintenance of telomeres

Brietta L. Pike and Jörg Heierhorst^*

St. Vincent's Institute of Medical Research, and Department of Medicine SVH, The University of Melbourne, Fitzroy, Victoria, Australia

^* To whom correspondence should be addressed. Email: jheierhorst{at}svi.edu.au.

DNA recombination plays critical roles in DNA repair and alternative telomere maintenance. Here we show that absence of the SQ/TQ cluster domain-containing protein Mdt1 (Ybl051c) renders Saccharomyces cerevisiae particularly hypersensitive to bleomycin, a drug that causes 3'-phospho-glycolate-blocked DNA double-strand breaks (DSBs). mdt1 also hypersensitizes partially recombination-defective cells to camptothecin-induced 3'-phospho-tyrosyl-protein-blocked DSBs. Remarkably, whereas mdt1 cells are unable to restore broken chromosomes after bleomycin treatment, they efficiently repair "clean" endonuclease-generated DSBs. Epistasis analyses indicate that MDT1 acts in the repair of bleomycin-induced DSBs by regulating the efficiency of the homologous recombination (HR) pathway as well as telomere-related functions of the KU complex. Moreover, mdt1 leads to severe synthetic growth defects with a deletion of the recombination facilitator and telomere-positioning factor gene CTF18 already in the absence of exogenous DNA damage. Importantly, mdt1 causes a dramatic shift from the usually prevalent type II to the less efficient type I pathway of recombinational telomere maintenance in the absence of telomerase in liquid senescence assays. As telomeres resemble protein-blocked DSBs, the results indicate that Mdt1 acts in a novel blocked-end-specific recombination pathway that is required for the efficiency of both drug-induced DSB repair and telomerase-independent telomere maintenance.