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Chromatin determinants impart camptothecin sensitivity

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Salguero, I 
Geisler, NJ 
Costanzo, V 


Camptothecin-induced locking of topoisomerase 1 on DNA generates a physical barrier to replication fork progression and creates topological stress. By allowing replisome rotation, absence of the Tof1/Csm3 complex promotes the conversion of impending topological stress to DNA catenation and causes camptothecin hypersensitivity. Through synthetic viability screening, we discovered that histone H4 K16 deacetylation drives the sensitivity of yeast cells to camptothecin and that inactivation of this pathway by mutating H4 K16 or the genes SIR1-4 suppresses much of the hypersensitivity of tof1∆ strains towards this agent. We show that disruption of rDNA or telomeric silencing does not mediate camptothecin resistance but that disruption of Sir1-dependent chromatin domains is sufficient to suppress camptothecin sensitivity in wild-type and tof1∆ cells. We suggest that topoisomerase 1 inhibition in proximity of these domains causes topological stress that leads to DNA hypercatenation, especially in the absence of the Tof1/Csm3 complex. Finally, we provide evidence of the evolutionarily conservation of this mechanism.



H4‐K16, SIR complex, Tof1, camptothecin, synthetic viability

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EMBO Reports

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EMBO Press
Cancer Research UK (18796)
Wellcome Trust (101126/Z/13/Z)
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
Research in the Jackson laboratory is funded by Cancer Research UK [C6/A11224, C6/A18796, C6946/A14492] and the Wellcome Trust [WT092096]; FP was supported by the Associazione Italiana per la Ricerca sul Cancro [10932] and the European Molecular Biology Organization [ALTF1287-2011]; IS, MH, and NJG were supported by the Wellcome Trust [101126/Z/13/Z (Strategic Award—COMSIG)] and [098051 to MH]; VC is supported by the Armenise-Harvard Foundation and the Fondazione Telethon.