Anti-cancer drug KP1019 modulates epigenetics and induces DNA damage response in Saccharomyces cerevisiae.

Abstract	KP1019 comprises a class of ruthenium compounds having promising anticancer activity. Here, we investigated the molecular targets of KP1019 using Saccharomyces cerevisiae as a model organism. Our results revealed that in the absence of the N-terminal tail of histone H3, the growth inhibitory effect of KP1019 was markedly enhanced. Furthermore, H3K56A or rtt109Δ mutants exhibit hypersensitivity for KP1019. Moreover, KP1019 evicts histones from the mononucleosome and interacts specifically with histone H3. We have also shown that KP1019 treatment causes induction of Ribonucleotide Reductase (RNR) genes and degradation of Sml1p. Our results also suggest that DNA damage induced by KP1019 is primarily repaired through double-strand break repair (DSBR). In summary, KP1019 targets histone proteins, with important consequences for DNA damage responses and epigenetics.
Authors	Vikash Singh, Gajendra Kumar Azad, Papita Mandal, M Amarendar Reddy, Raghuvir S Tomar
Journal	FEBS letters (FEBS Lett) Vol. 588 Issue 6 Pg. 1044-52 (Mar 18 2014) ISSN: 1873-3468 [Electronic] England
PMID	24561198 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Chemical References	Antineoplastic Agents Chromatin Histones Indazoles Organometallic Compounds Ruthenium Compounds Saccharomyces cerevisiae Proteins indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III)) Histone Deacetylases
Topics	Antineoplastic Agents (pharmacology) Chromatin (metabolism) DNA Damage DNA Repair Drug Screening Assays, Antitumor Epigenesis, Genetic (drug effects) G2 Phase Cell Cycle Checkpoints (drug effects) Gene Expression Gene Expression Regulation, Fungal (drug effects) Histone Deacetylases (metabolism) Histones (metabolism) Humans Indazoles (pharmacology) Microbial Viability (drug effects) Organometallic Compounds (pharmacology) Protein Processing, Post-Translational Ruthenium Compounds Saccharomyces cerevisiae (drug effects, genetics) Saccharomyces cerevisiae Proteins (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!