Anti‐cancer drug KP1019 modulates epigenetics and induces DNA damage response in Saccharomyces cerevisiae. Issue 6 (20th February 2014)

• Record Type: Journal Article
• Authors: Singh, Vikash; Azad, Gajendra Kumar; Mandal, Papita; Amarendar Reddy, M.; Tomar, Raghuvir S.
• Is Part Of: FEBS letters. Volume 588:Issue 6(2014)
• Page Start: 1044
• Page End: 1052
• Publication Date: 2014-02-20
• Subjects: KP1019 -- Anti-cancer drug -- Epigenetics -- Histones -- DNA damage response; Biochemistry -- Periodicals; Biophysics -- Periodicals; Molecular biology -- Periodicals; Biochimie -- Périodiques; Biochemistry; Biophysics; Molecular biology; Periodicals; 572.05
• DOI: 10.1016/j.febslet.2014.02.017
• Languages: English
• ISSNs: 0014-5793

Abstract

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. Abstract : Histones and their modifying enzymes provide tolerance to KP019. KP1019 treatment causes activation of DNA damage checkpoint kinase pathway. KP1019 activates DNA damage response by inducing RNR genes.