Oncotarget

Research Papers:

MERIT40-dependent recruitment of tankyrase to damaged DNA and its implication for cell sensitivity to DNA-damaging anticancer drugs

Keiji Okamoto, Tomokazu Ohishi, Mika Kuroiwa, Shun-ichiro Iemura, Tohru Natsume and Hiroyuki Seimiya _

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Oncotarget. 2018; 9:35844-35855. https://doi.org/10.18632/oncotarget.26312

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Abstract

Keiji Okamoto1, Tomokazu Ohishi1,4, Mika Kuroiwa1,2, Shun-ichiro Iemura3,5, Tohru Natsume3 and Hiroyuki Seimiya1,2

1Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan

2Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Koto-ku, Tokyo, Japan

3Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Koto-ku, Tokyo, Japan

4Current address: Institute of Microbial Chemistry (BIKAKEN), Numazu, Shizuoka, Japan

5Current address: Translational Research Center, Fukushima Medical University, Fukushima, Japan

Correspondence to:

Hiroyuki Seimiya, email: hseimiya@jfcr.or.jp

Keywords: tankyrase; MERIT40; DNA damage response; DNA repair; cancer chemotherapy

Received: June 11, 2018    Accepted: October 24, 2018    Published: November 09, 2018

ABSTRACT

Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, regulates various intracellular responses, such as telomere maintenance, Wnt/β-catenin signaling and cell cycle progression through its interactions with multiple target proteins. Tankyrase contains a long stretch of 24 ankyrin repeats that are further divided into five subdomains, called ANK repeat clusters (ARCs). Each ARC works as an independent ligand-binding unit, which implicates tankyrase as a platform for multiple protein-protein interactions. Furthermore, tankyrase distributes to various intracellular loci, suggesting potential distinct but yet unidentified physiological functions. To explore the novel functions of tankyrase, we performed liquid chromatography-mass spectrometry analysis and identified the BRE-BRCC36-MERIT40 complex, a regulator of homologous recombination, as tankyrase-binding proteins. Among the complex components, MERIT40 was directly associated with tankyrase via a tankyrase-binding consensus motif, as previously reported. In X-ray-irradiated non-small cell lung cancer cells, tankyrase localized to DNA double-stranded break sites in a MERIT40-dependent manner. MERIT40 knockdown increased the cell sensitivity to X-ray, whereas the wild-type, but not the tankyrase-unbound mutant, MERIT40 rescued the phenotype of the knockdown cells. Tankyrase inhibitors, such as G007-LK and XAV939, increased the cellular sensitivity to X-ray irradiation and anticancer drugs that induce DNA double-stranded breaks. These observations suggest that tankyrase plays a role in the DNA damage repair response and implicates a potential therapeutic utility of tankyrase inhibitors in combination treatments with DNA-damaging anticancer drugs.


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