RETRACTED: 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, Yoshinobu

doi:10.1016/j.bbrep.2018.10.014

Cited by 5 publications

(4 citation statements)

References 34 publications

(43 reference statements)

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“…Interestingly, we noticed that the doublecortin-like kinase DCLK1 (also known as DCAMKL1) is enriched in our BioIDs under replication stress. Various studies have demonstrated the importance of DCLK1 during the DNA damage response [47,48], and our data suggest that DCLK1 may play a role in the regulation of the classical RAD51 paralogs during the response to replication stress.…”

Section: Plos Geneticssupporting

confidence: 62%

Systematic proximal mapping of the classical RAD51 paralogs unravel functionally and clinically relevant interactors for genome stability

et al. 2022

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Homologous recombination (HR) plays an essential role in the maintenance of genome stability by promoting the repair of cytotoxic DNA double strand breaks (DSBs). More recently, the HR pathway has emerged as a core component of the response to replication stress, in part by protecting stalled replication forks from nucleolytic degradation. In that regard, the mammalian RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) have been involved in both HR-mediated DNA repair and collapsed replication fork resolution. Still, it remains largely obscure how they participate in both processes, thereby maintaining genome stability and preventing cancer development. To gain better insight into their contribution in cellulo, we mapped the proximal interactome of the classical RAD51 paralogs using the BioID approach. Aside from identifying the well-established BCDX2 and CX3 sub-complexes, the spliceosome machinery emerged as an integral component of our proximal mapping, suggesting a crosstalk between this pathway and the RAD51 paralogs. Furthermore, we noticed that factors involved RNA metabolic pathways are significantly modulated within the BioID of the classical RAD51 paralogs upon exposure to hydroxyurea (HU), pointing towards a direct contribution of RNA processing during replication stress. Importantly, several members of these pathways have prognostic potential in breast cancer (BC), where their RNA expression correlates with poorer patient outcome. Collectively, this study uncovers novel functionally relevant partners of the different RAD51 paralogs in the maintenance of genome stability that could be used as biomarkers for the prognosis of BC.

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Section: Plos Geneticssupporting

confidence: 62%

Systematic proximal mapping of the classical RAD51 paralogs unravel functionally and clinically relevant interactors for genome stability

et al. 2022

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“…It was suggested that DCLK1 regulates migration, invasion and cell motility via activation of EMT (43), an important process for cancer initiation, cancer metastasis, and secondary tumor formation. However, expression of DCLK1 was also associated with impaired DNA repair (57,58), upregulation of WNT/b-catenin (59,60), RAS (13,61), PI3K/AKT (62) and VEGF (63,64) signaling, suggesting a multifaceted role of DCLK1 in cancer initiation and progression. Concordantly, our analysis of TCGA-HNSC dataset indicates that in HNSCC, tumors expressing higher DCLK1 mRNA levels were enriched for pathways that have been implicated in the EMT and CSC maintenance (such as NOTCH, WNT, TGFb, and hedgehog signaling), as well as for RAS and angiogenesis cascades.…”

Section: Discussionmentioning

confidence: 99%

Doublecortin-Like Kinase 1 (DCLK1) Is a Novel NOTCH Pathway Signaling Regulator in Head and Neck Squamous Cell Carcinoma

Broner

Trujillo

Korzinkin³

et al. 2021

Front. Oncol.

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Despite recent advancements, the 5 year survival of head and neck squamous cell carcinoma (HNSCC) hovers at 60%. DCLK1 has been shown to regulate epithelial-to-mesenchymal transition as well as serving as a cancer stem cell marker in colon, pancreatic and renal cancer. Although it was reported that DCLK1 is associated with poor prognosis in oropharyngeal cancers, very little is known about the molecular characterization of DCLK1 in HNSCC. In this study, we performed a comprehensive transcriptome-based computational analysis on hundreds of HNSCC patients from TCGA and GEO databases, and found that DCLK1 expression positively correlates with NOTCH signaling pathway activation. Since NOTCH signaling has a recognized role in HNSCC tumorigenesis, we next performed a series of in vitro experiments in a collection of HNSCC cell lines to investigate the role of DCLK1 in NOTCH pathway regulation. Our analyses revealed that DCLK1 inhibition, using either a pharmacological inhibitor or siRNA, resulted in substantially decreased proliferation, invasion, migration, and colony formation. Furthermore, these effects paralleled downregulation of active NOTCH1, and its downstream effectors, HEY1, HES1 and HES5, whereas overexpression of DCLK1 in normal keratinocytes, lead to an upregulation of NOTCH signaling associated with increased proliferation. Analysis of 233 primary and 40 recurrent HNSCC cancer biopsies revealed that high DCLK1 expression was associated with poor prognosis and showed a trend towards higher active NOTCH1 expression in tumors with elevated DCLK1. Our results demonstrate the novel role of DCLK1 as a regulator of NOTCH signaling network and suggest its potential as a therapeutic target in HNSCC.

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“…Given that the temporal and spatial expression pattern of doublecortin is very similar to that of DCLK1, DCLK1 is proposed to have functions similar to that of doublecortin ( 20 , 21 ). Thus, it may serve a role in neuronal migration, axon transport, synapse maturation and brain development ( 21 – 24 ). Furthermore, DCLK1 has two isoforms of varying lengths because of the epithelial changes that occur with different functions, where the shorter isoform DCLK1-S induces tumorigenesis in colorectal cancer (CRC) ( 7 , 25 , 26 ).…”

Section: Functions Of Dclk1 and Its Role In Cancermentioning

confidence: 99%

DCLK1 and its interaction partners: An effective therapeutic target for colorectal cancer (Review)

et al. 2021

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Doublecortin-like kinase protein 1 (DCLK1) is a microtubule-associated protein with a C-terminal serine/threonine kinase domain. Its expression was first reported in radial glial cells, where it serves an essential role in early neurogenesis, and since then, other functions of the DCLK1 protein have also been identified. Initially considered to be a marker of quiescent gastrointestinal and pancreatic stem cells, DCLK1 has recently been identified in the gastrointestinal tract as a marker of tuft cells. It has also been implicated in different types of cancer, where it regulates several vital pathways, such as Kras signaling. However, its underlying molecular mechanisms remain unclear. The present review discusses the different roles of DCLK1 and its interactions with other proteins that are homologically similar to DCLK1 to develop a novel therapeutic strategy to target cancer cells more accurately.

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

Cited by 5 publications

References 34 publications

Systematic proximal mapping of the classical RAD51 paralogs unravel functionally and clinically relevant interactors for genome stability

Systematic proximal mapping of the classical RAD51 paralogs unravel functionally and clinically relevant interactors for genome stability

Doublecortin-Like Kinase 1 (DCLK1) Is a Novel NOTCH Pathway Signaling Regulator in Head and Neck Squamous Cell Carcinoma

DCLK1 and its interaction partners: An effective therapeutic target for colorectal cancer (Review)

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