Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability.
Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability.
复制标题
DOI：
10.1016/j.bbrep.2018.10.014
复制
发表时间：
2018-12
影响因子：
2.7
通讯作者：
Hata Y
中科院分区：
文献类型：
--
作者：
Lu Y;Maruyama J;Kuwata K;Fukuda H;Iwasa H;Arimoto-Matsuzaki K;Sugimura H;Hata Y
双皮质素样激酶1（DCLK 1）是一种丝氨酸/苏氨酸激酶，具有两个双皮质素（DCX）结构域。DCLK 1通过DCX结构域与微管结合并调节微管聚合。已知DCLK 1在癌症干细胞中表达，并为癌细胞提供肿瘤起始能力。累积的临床证据支持DCLK 1与肿瘤侵袭性相关，并且是各种人类癌症的重要预后标志物。然而，DCLK 1引起肿瘤发生的机制尚未阐明。在这项研究中，我们发现DCLK 1使人乳腺上皮MCF 10A细胞在无血清培养基中漂浮条件下形成球体，这让人想起乳腺上皮干细胞形成的乳腺球。我们证明了DCLK 1导致MCF 10A细胞染色质不稳定。DCLK 1在人结肠癌HCT 116和肺癌H1299细胞中损害DNA修复。激酶阴性DCLK 1突变体和与微管无关的突变体损害DNA修复。总之，DCLK 1通过基因组不稳定性干扰DNA修复并诱导肿瘤发生，这种功能不依赖于激酶活性和微管的调节。双皮质素样激酶1（DCLK 1）赋予癌细胞干性。表达DCLK 1的乳腺上皮细胞在漂浮条件下形成球体。DCLK 1在乳腺上皮细胞中引起强烈的染色体异常。DCLK 1损害癌细胞中的DNA修复。激酶阴性的DCLK 1显示类似的作用。
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. Doublecortin-like kinase 1 (DCLK1) confers stemness to cancer cells. Mammary epithelial cells expressing DCLK1 form spheres under floating condition. DCLK1 causes robust chromosomal abnormalities in mammary epithelial cells. DCLK1 impairs DNA repair in cancer cells. The kinase-negative DCLK1 shows similar effects.
登录
查看更多内容
影响因子：
34.7
作者：
Lisman, John;Yasuda, Ryohei;Raghavachari, Sridhar
通讯作者：
Raghavachari, Sridhar
影响因子：
16
作者：
Liu, Judy S.;Schubert, Christian R.;Fu, Xiaoqin;Fourniol, Franck J.;Jaiswal, Jyoti K.;Houdusse, Anne;Stultz, Collin M.;Moores, Carolyn A.;Walsh, Christopher A.
通讯作者：
Walsh, Christopher A.
影响因子：
--
作者：
Chandrakesan P;Weygant N;May R;Qu D;Chinthalapally HR;Sureban SM;Ali N;Lightfoot SA;Umar S;Houchen CW
通讯作者：
Houchen CW
影响因子：
2.8
作者：
Gagliardi, Giuseppe;Moroz, Krzysztof;Bellows, Charles F.
通讯作者：
Bellows, Charles F.
影响因子：
6.4
作者：
Liu, Weiying;Wang, Shixing;Tang, Hua
通讯作者：
Tang, Hua