title: 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.affiliation: Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal 462023, India.
authors.forename: Vikash
authors.initials: V
authors.lastname: Singh
authors.affiliation: Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal 462023, India.
authors.forename: Gajendra Kumar
authors.initials: GK
authors.lastname: Azad
authors.affiliation: Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal 462023, India.
authors.forename: Papita
authors.initials: P
authors.lastname: Mandal
authors.affiliation: Department of Chemistry, Indian Institute of Science Education and Research, Bhopal 462023, India.
authors.forename: M Amarendar
authors.initials: MA
authors.lastname: Reddy
authors.affiliation: Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal 462023, India. Electronic address: rst@iiserb.ac.in.
authors.forename: Raghuvir S
authors.initials: RS
authors.lastname: Tomar
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004354:Drug Screening Assays, Antitumor; D044127:Epigenesis, Genetic / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015870:Gene Expression; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D050296:Microbial Viability / Q000187:drug effects; D009942:Organometallic Compounds / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D017975:Ruthenium Compounds; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002843:Chromatin; D006657:Histones; D007191:Indazoles; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; D029701:Saccharomyces cerevisiae Proteins; C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III)); D006655:Histone Deacetylases
keywords: Anti-cancer drug; DNA damage response; Epigenetics; Histones; KP1019