DNA-PK as an Emerging Therapeutic Target in Cancer

Mohiuddin, Ismail; Kang, Min H.

doi:10.3389/fonc.2019.00635

Cited by 145 publications

(129 citation statements)

References 87 publications

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“…1f). Each one yielded increases in CRISPR-del efficiency to varying degrees, correlating with published differences on the inhibition potency 57 . As expected based on previous literature, KU57788 gave the strongest effect 57 and DMNB gave the weakest effect, likely due to its high IC50.…”

Section: Temporary Inhibition Of Dna-pk During Dsb Formation Increasesupporting

confidence: 63%

Enhancing CRISPR deletion via pharmacological delay of DNA-PK

Bosch

Medová

Esposito

et al. 2020

Preprint

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CRISPR-Cas9 deletion (CRISPR-del) is the leading approach for eliminating DNA from mammalian cells and underpins a variety of genome-editing applications. Target DNA, defined by a pair of double strand breaks (DSBs), is removed during non-homologous end-joining (NHEJ). However, the low efficiency of CRISPR-del results in laborious experiments and false negative results. Using an endogenous reporter system, we demonstrate that temporary inhibition of DNA-dependent protein kinase (DNA-PK) -an early step in NHEJ -yields up to 17-fold increase in DNA deletion. This is observed across diverse cell lines, gene delivery methods, commercial inhibitors and guide RNAs, including those that otherwise display negligible activity. Importantly, the method is compatible with pooled functional screens employing lentivirally-delivered guide RNAs. Thus, delaying the kinetics of NHEJ relative to DSB formation is a simple and effective means of enhancing CRISPR-deletion.

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Section: Temporary Inhibition Of Dna-pk During Dsb Formation Increasesupporting

confidence: 63%

Enhancing CRISPR deletion via pharmacological delay of DNA-PK

Bosch

Medová

Esposito

et al. 2020

Preprint

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“…In our study, we demonstrate the same effect for breast cancer. A decrease in this key DNA repair protein is known to sensitize breast cancer to radiation [43] and the protein has been suggested as a therapeutic target [44]. Interestingly, the decrease in DNA-PKcs may also explain why we were unable to see changes in double strand breaks via γH2AX assay.…”

mentioning

confidence: 80%

Knockdown of Musashi RNA Binding Proteins Decreases Radioresistance but Enhances Cell Motility and Invasion in Triple-Negative Breast Cancer

Troschel

Minte

Ismail

et al. 2020

IJMS

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The therapeutic potential of Musashi (MSI) RNA-binding proteins, important stemness-associated gene expression regulators, remains insufficiently understood in breast cancer. This study identifies the interplay between MSI protein expression, stem cell characteristics, radioresistance, cell invasiveness and migration. MSI-1, MSI-2 and Notch pathway elements were investigated via quantitative polymerase chain reaction (qPCR) in 19 triple-negative breast cancer samples. Measurements were repeated in MDA-MB-231 cells after MSI-1 and -2 siRNA-mediated double knockdown, with further experiments performed after MSI silencing. Flow cytometry helped quantify expression of CD44 and leukemia inhibitory factor receptor (LIFR), changes in apoptosis and cell cycle progression. Proliferation and irradiation-induced effects were assessed using colony formation assays. Radiation-related proteins were investigated via Western blots. Finally, cell invasion assays and digital holographic microscopy for cell migration were performed. MSI proteins showed strong correlations with Notch pathway elements. MSI knockdown resulted in reduction of stem cell marker expression, cell cycle progression and proliferation, while increasing apoptosis. Cells were radiosensitized as radioresistance-conferring proteins were downregulated. However, MSI-silencing-mediated LIFR downregulation resulted in enhanced cell invasion and migration. We conclude that, while MSI knockdown results in several therapeutically desirable consequences, enhanced invasion and migration need to be counteracted before knockdown advantages can be fully exploited.

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“…CDC45 plays a key role in late G1, as it is a key element of the DNA replication machinery; thus, it is deemed as a key element of the pathogenic network in CC [ 38 ]. Furthermore, DNA-PK, a dynamic enzyme involved in DNA double-stranded breaks repair pathway [ 39 ], has been proposed as a therapeutic target [ 40 , 41 ], while E2F1 plays critical roles in both cell cycle regulation and chromosome segregation. It has been reported that E2F1 may promote DNA replication and cancer cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Identification of Core Genes Involved in the Progression of Cervical Cancer Using an Integrative mRNA Analysis

Dudea-Simon

Mihu

Irimie

et al. 2020

IJMS

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In spite of being a preventable disease, cervical cancer (CC) remains at high incidence, and it has a significant mortality rate. Although hijacking of the host cellular pathway is fundamental for developing a better understanding of the human papillomavirus (HPV) pathogenesis, a major obstacle is identifying the central molecular targets involved in HPV-driven CC. The aim of this study is to investigate transcriptomic patterns of HPV-infected and normal tissues to identify novel prognostic markers. Analyses of functional enrichment and interaction networks reveal that altered genes are mainly involved in cell cycle, DNA damage, and regulated cell-to-cell signaling. Analysis of The Cancer Genome Atlas (TCGA) data has suggested that patients with unfavorable prognostics are more likely to have DNA repair defects attributed, in most cases, to the presence of HPV. However, further studies are needed to fully unravel the molecular mechanisms of such genes involved in CC.

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DNA-PK as an Emerging Therapeutic Target in Cancer

Cited by 145 publications

References 87 publications

Enhancing CRISPR deletion via pharmacological delay of DNA-PK

Enhancing CRISPR deletion via pharmacological delay of DNA-PK

Knockdown of Musashi RNA Binding Proteins Decreases Radioresistance but Enhances Cell Motility and Invasion in Triple-Negative Breast Cancer

Identification of Core Genes Involved in the Progression of Cervical Cancer Using an Integrative mRNA Analysis

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