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Biochem Biophys Rep. 2018 Oct 30;16:130-137. doi: 10.1016/j.bbrep.2018.10.014. eCollection 2018 Dec.

Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability.

Author information

1
Department of Medical Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
2
Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya 464-8601, Japan.
3
Agilent Technologies Research Alliance Laboratory, Graduate School of Science, Osaka University, Osaka 565-0871, Japan.
4
Agilent Technologies Japan, Ltd., Hachioji-shi, Tokyo 192-8510, Japan.
5
Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu 431-3152, Japan.
6
Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

Abstract

Doublecortin-like kinase 1 (DCLK1) is a serine/threonine-kinase with two doublecortin (DCX) domains. DCLK1 is associated with microtubules via DCX domains and regulates microtubule polymerization. DCLK1 is known to be expressed in cancer stem cells and provides cancer cells with tumor-initiating capacity. Accumulating clinical evidence supports that DCLK1 is associated with tumor aggressiveness and is an important prognostic marker in various human cancers. However, the mechanism, by which DCLK1 causes oncogenesis, is not yet elucidated. In this study, we showed that DCLK1 empowers human mammary epithelial MCF10A cells to form spheres under floating condition in serum-free medium, which are reminiscent of mammospheres formed by mammary epithelial stem cells. We demonstrated that DCLK1 causes chromatin instability in MCF10A cells. DCLK1 impairs DNA repairs in human colon cancer HCT116 and lung cancer H1299 cells. The kinase-negative DCLK1 mutant and the mutant that is not associated with microtubules compromise DNA repair. In conclusion, DCLK1 interferes with DNA repair and induces tumorigenesis through genomic instability and this function is independent of the kinase activity and the regulation of microtubules.

KEYWORDS:

Chromatin instability; DCLK1; DNA repair

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