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

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 cap...

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Autores principales: Lu, Yuxiong, Maruyama, Junichi, Kuwata, Keiko, Fukuda, Hiroyuki, Iwasa, Hiroaki, Arimoto-Matsuzaki, Kyoko, Sugimura, Haruhiko, Hata, Yutaka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216093/
https://www.ncbi.nlm.nih.gov/pubmed/30417131
http://dx.doi.org/10.1016/j.bbrep.2018.10.014
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author Lu, Yuxiong
Maruyama, Junichi
Kuwata, Keiko
Fukuda, Hiroyuki
Iwasa, Hiroaki
Arimoto-Matsuzaki, Kyoko
Sugimura, Haruhiko
Hata, Yutaka
author_facet Lu, Yuxiong
Maruyama, Junichi
Kuwata, Keiko
Fukuda, Hiroyuki
Iwasa, Hiroaki
Arimoto-Matsuzaki, Kyoko
Sugimura, Haruhiko
Hata, Yutaka
author_sort Lu, Yuxiong
collection PubMed
description 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.
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spelling pubmed-62160932018-11-09 Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability Lu, Yuxiong Maruyama, Junichi Kuwata, Keiko Fukuda, Hiroyuki Iwasa, Hiroaki Arimoto-Matsuzaki, Kyoko Sugimura, Haruhiko Hata, Yutaka Biochem Biophys Rep Research Article 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. Elsevier 2018-10-30 /pmc/articles/PMC6216093/ /pubmed/30417131 http://dx.doi.org/10.1016/j.bbrep.2018.10.014 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Lu, Yuxiong
Maruyama, Junichi
Kuwata, Keiko
Fukuda, Hiroyuki
Iwasa, Hiroaki
Arimoto-Matsuzaki, Kyoko
Sugimura, Haruhiko
Hata, Yutaka
Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability
title Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability
title_full Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability
title_fullStr Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability
title_full_unstemmed Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability
title_short Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability
title_sort doublecortin-like kinase 1 compromises dna repair and induces chromosomal instability
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216093/
https://www.ncbi.nlm.nih.gov/pubmed/30417131
http://dx.doi.org/10.1016/j.bbrep.2018.10.014
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