Telomere-related functions of yeast KU in the repair of bleomycin-induced DNA damage.
Bleomycins are small glycopeptide cancer chemotherapeutics that give rise to 3'-modified DNA double-strand breaks (DSBs). In Saccharomyces cerevisiae, DSBs are predominantly repaired by RAD52-dependent homologous recombination (HR) with some support by Yku70/Yku80 (KU)-dependent pathways. The main DSB repair function of KU is believed to be as part of the non-homologous end-joining (NHEJ) pathway, but KU also functions in a "chromosome healing" pathway that seals DSBs by de novo telomere addition. We report here that rad52Deltayku70Delta double mutants are considerably more bleomycin hypersensitive than rad52Deltalig4Delta cells that lack the NHEJ-specific DNA ligase 4. Moreover, the telomere-specific KU mutation yku80-135i also dramatically increases rad52Delta bleomycin hypersensitivity, almost to the level of rad52Deltayku80Delta. The results indicate that telomere-specific functions of KU play a more prominent role in the repair of bleomycin-induced damage than its NHEJ functions, which could have important clinical implications for bleomycin-based combination chemotherapies.
Tam
Angela T Y
AT
St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Vic. 3065, Australia.
Pike
Brietta L
BL
Hammet
Andrew
A
Heierhorst
Jörg
J
D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D034961:Antigens, Nuclear / Q000235:genetics / Q000502:physiology*; D001761:Bleomycin / Q000633:toxicity*; D004249:DNA Damage; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000502:physiology; 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*; D000072200:Ku Autoantigen; D050296:Microbial Viability / Q000187:drug effects / Q000235:genetics; D009154:Mutation; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics / Q000502:physiology; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology; D016615:Telomere / Q000235:genetics / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D034961:Antigens, Nuclear; D004271:DNA, Fungal; D004268:DNA-Binding Proteins; C497197:RAD52 protein, S cerevisiae; D051721:Rad52 DNA Repair and Recombination Protein; D029701:Saccharomyces cerevisiae Proteins; D001761:Bleomycin; D000072200:Ku Autoantigen; D011088:DNA Ligases; D000072481:DNA Ligase ATP