Chromatin determinants impart camptothecin sensitivity.
EMBO Rep
; 18(6): 1000-1012, 2017 06.
Article
en En
| MEDLINE
| ID: mdl-28389464
ABSTRACT
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Camptotecina
/
Cromatina
/
Proteínas de Saccharomyces cerevisiae
Tipo de estudio:
Diagnostic_studies
Límite:
Humans
Idioma:
En
Año:
2017
Tipo del documento:
Article