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FEBS Lett. 2014 Mar 18;588(6):1044-52. doi: 10.1016/j.febslet.2014.02.017. Epub 2014 Feb 20.

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

Author information

1
Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal 462023, India.
2
Department of Chemistry, Indian Institute of Science Education and Research, Bhopal 462023, India.
3
Laboratory of Chromatin Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal 462023, India. Electronic address: rst@iiserb.ac.in.

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.

KEYWORDS:

Anti-cancer drug; DNA damage response; Epigenetics; Histones; KP1019

PMID:
24561198
DOI:
10.1016/j.febslet.2014.02.017
[Indexed for MEDLINE]
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