Chemogenomic profiling of the cellular effects associated with histone H3 acetylation impairment by a quinoline-derived compound.
We report the results of a chemogenomic profiling aimed to explore the mode of action of a quinolic analogue of the p300 histone acetyltransferase (HAT) inhibitor anacardic acid, named MC1626. This compound reduced histone H3 acetylation in a dose-dependent manner and the HATs Gcn5 and Rtt109, which specifically target H3 lysines, were the only ones that caused chemical-genetic synthetic sickness with MC1626 when mutated. Deletion of specific Gcn5 (e.g., Ada1) and Rtt109 (e.g., Asf1) multiprotein complex components also enhanced MC1626 sensitivity. In addition to N-terminal H3 lysines, MC1626 inhibits H3-K56 acetylation, a histone modification that, in yeast, is exclusively supported by Rtt109 and indirectly influences DNA integrity. Several DNA repair mutants were found to be sensitive to MC1626. Functional links between histone acetylation impairment by MC1626 and mitochondrion as well as cytoskeleton functionality were also revealed, thus extending the range of non-nuclear processes that are influenced by histone acetylation.
Ruotolo
Roberta
R
Dipartimento di Biochimica e Biologia Molecolare, Università di Parma, Parma, Italy.
Tosi
Federica
F
Vernarecci
Stefano
S
Ballario
Paola
P
Mai
Antonello
A
Filetici
Patrizia
P
Ottonello
Simone
S
D000107:Acetylation / Q000187:drug effects; D017353:Gene Deletion; D020869:Gene Expression Profiling; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests / Q000379:methods; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000187:drug effects*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D051548:Histone Acetyltransferases; D006657:Histones; D046912:Multiprotein Complexes; D011804:Quinolines; D029701:Saccharomyces cerevisiae Proteins; C504219:MC1626; C501392:GCN5 protein, S cerevisiae; D000099224:p300-CBP-Associated Factor; C517120:Rtt109 protein, S cerevisiae