Mdt1 facilitates efficient repair of blocked DNA double-strand breaks and recombinational maintenance of telomeres.
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). mdt1Delta also hypersensitizes partially recombination-defective cells to camptothecin-induced 3'-phospho-tyrosyl protein-blocked DSBs. Remarkably, whereas mdt1Delta 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 pathway as well as telomere-related functions of the KU complex. Moreover, mdt1Delta 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, mdt1Delta 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.
Pike
Brietta L
BL
St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC 3065, Australia.
Heierhorst
Jörg
J
D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D034961:Antigens, Nuclear / Q000235:genetics / Q000502:physiology; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D002166:Camptothecin / Q000633:toxicity; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004271:DNA, Fungal / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004843:Epistasis, Genetic; D000072200:Ku Autoantigen; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016615:Telomere / Q000235:genetics / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D034961:Antigens, Nuclear; D000972:Antineoplastic Agents, Phytogenic; D004271:DNA, Fungal; D004268:DNA-Binding Proteins; C523554:PIN4 protein, S cerevisiae; D051721:Rad52 DNA Repair and Recombination Protein; D029701:Saccharomyces cerevisiae Proteins; D001761:Bleomycin; D000072200:Ku Autoantigen; D002166:Camptothecin