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

Abstract

a b s t r a c t 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 rtt109D 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.

RuIII Complexes for Anticancer Therapy: The Importance of Being Nucleolipidic

“…In principle, these compounds offer several advantages over antitumour Pt II complexes currently used clinically: reduced toxicity, different mechanisms of action, the prospect of non-cross-resistance [23,24] and a wide spectrum of activity. [11,26] They have the general formula (HB)[Ru III B 2 Cl 4 ] (where B is a heterocyclic base) and typically include axial heterocyclic nitrogen donor ligands and equatorial chlorides, with charge compensation provided by protonated nitrogen heterocycles -as is the case for KP1019 [27][28][29][30] (Figure 1), developed by Keppler Although the mechanism(s) of action and the main target(s) of these ruthenium-based drugs have not yet been unambiguously determined, a large amount of valuable data on their in vitro and in vivo behaviour has been obtained, [36][37][38] summarized in several reviews. [11,26] They have the general formula (HB)[Ru III B 2 Cl 4 ] (where B is a heterocyclic base) and typically include axial heterocyclic nitrogen donor ligands and equatorial chlorides, with charge compensation provided by protonated nitrogen heterocycles -as is the case for KP1019 [27][28][29][30] (Figure 1), developed by Keppler Although the mechanism(s) of action and the main target(s) of these ruthenium-based drugs have not yet been unambiguously determined, a large amount of valuable data on their in vitro and in vivo behaviour has been obtained, [36][37][38] summarized in several reviews.…”

Evidence that the antiproliferative effects of auranofin in Saccharomyces cerevisiae arise from inhibition of mitochondrial respiration

“…Yeast is, indeed, an excellent biological model to monitor and identify the biochemical mechanisms of cytotoxic compounds (Matuo et al, 2012). A number of previous studies described the effects of various metal based anticancer drugs such as cisplatin and ruthenium compounds in yeast providing new valuable mechanistic information (Cunha et al, 2013;Singh et al, 2014;Stevens et al, 2013;Wang et al, 2012).…”

Epigenetic modulation by inorganic metal complexes

“…Recently, Tomar and co-workers utilized Saccharomyces cerevisiae as a model organism to elucidate the molecular target of KP1019 [53]. K P1019 was revealed to eject histones from nucleosomal DNA and interact with histone H3, but without affecting acetylated H4K8 in vitro.…”

“…Chemical structure of 9 (KP1019)[53].Page 13 of 32A c c e p t e d M a n u s c r i p t 13 4. Metal complexes targeting chromatin-modifying enzymes 4.1.…”