Role of PRKDC in cancer initiation, progression, and treatment

Chen, Yu; Li, Yi; Xiong, Jiani; Liu, Bin; Wang, Xuefeng; Li, Jun; Lin, Jing; Fei, Zhaodong; Zheng, Xiaobin; Chen, Chuanben

doi:10.1186/s12935-021-02229-8

Cited by 30 publications

(24 citation statements)

References 68 publications

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“…Only two genes, Prkdc and Dyrk1a, were found among the 20 most significant candidates from both the 2D and 3D screenings ( Supplementary Table S1 ). Protein kinase, DNA-activated, catalytic subunit (PRKDC), alternatively referred to as DNA-PKcs, functions as a molecular sensor of DNA damage, which engaged in the non-homologous end joining (NHEJ) pathway for a DNA double-strand break (DSB) repair process [ 25 ]. All four sgRNAs targeting the second candidate, DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A), were significantly reduced in both 2D and 3D screens ( Figure 1 F,G).…”

Section: Resultsmentioning

confidence: 99%

CRISPR-Cas9 Screen Identifies DYRK1A as a Target for Radiotherapy Sensitization in Pancreatic Cancer

Lan

Zeng

Zhang

et al. 2022

Cancers

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Although radiation therapy has recently made great advances in cancer treatment, the majority of patients diagnosed with pancreatic cancer (PC) cannot achieve satisfactory outcomes due to intrinsic and acquired radioresistance. Identifying the molecular mechanisms that impair the efficacy of radiotherapy and targeting these pathways are essential to improve the radiation response of PC patients. Our goal is to identify sensitive targets for pancreatic cancer radiotherapy (RT) using the kinome-wide CRISPR-Cas9 loss-of-function screen and enhance the therapeutic effect through the development and application of targeted inhibitors combined with radiotherapy. We transduced pancreatic cancer cells with a protein kinase library; 2D and 3D library cells were irradiated daily with a single dose of up to 2 Gy for 4 weeks for a total of 40 Gy using an X-ray generator. Sufficient DNA was collected for next-generation deep sequencing to identify candidate genes. In this study, we identified several cell cycle checkpoint kinases and DNA damage related kinases in 2D- and 3D-cultivated cells, including DYRK1A, whose loss of function sensitizes cells to radiotherapy. Additionally, we demonstrated that the harmine-targeted suppression of DYRK1A used in conjunction with radiotherapy increases DNA double-strand breaks (DSBs) and impairs homologous repair (HR), resulting in more cancer cell death. Our results support the use of CRISPR-Cas9 screening to identify new therapeutic targets, develop radiosensitizers, and provide novel strategies for overcoming the tolerance of pancreatic cancer to radiotherapy.

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Section: Resultsmentioning

confidence: 99%

CRISPR-Cas9 Screen Identifies DYRK1A as a Target for Radiotherapy Sensitization in Pancreatic Cancer

Lan

Zeng

Zhang

et al. 2022

Cancers

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“…Protein kinase, DNA-activated, catalytic polypeptide (PRKDC) encodes the DNA-dependent protein kinase catalytic subunit protein, which plays an important role in nonhomologous end joining of DNA double-strand breaks ( 55 ). Loss of PRKDC expression is associated with impaired DNA repair ( 56 ).…”

Section: The Status Quo and Efficacy Prediction Of Immunotherapymentioning

confidence: 99%

Evaluation of immunotherapy efficacy in gynecologic cancer

Jiang

Wu²,

Li³

2023

Front. Immunol.

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Various immunotherapies have demonstrated remarkable success over the past few decades, and have been approved for the treatment of different cancer types. However, patient responses to immunotherapy are variable, and approximately 50% of cases are refractory to these agents. Tumor biomarker-based stratification of cases may therefore help identify subpopulations that are sensitive/resistant to immunotherapy; it may also improve prediction of response in various cancers including gynecologic cancer. These biomarkers include the tumor mutational burden, microsatellite instability, mismatch repair deficiency, T cell-inflamed gene expression profile, programmed cell death protein 1 ligand 1, tumor-infiltrating lymphocytes, and numerous other genomic alterations. Future directions in the treatment of gynecologic cancer include the utilization of these biomarkers to select ideal candidates. This review focused on recent advances in the predictive ability of molecular biomarkers in patients with gynecologic cancer who undergo immunotherapy. The most recent developments in combined immunotherapy and targeted therapy strategies and novel immune interventions against gynecologic cancers have also been discussed.

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“…Another AIRE partner is a DNA-dependent protein kinase (DNA-PK) that phosphorylates residues of threonine and serine (in sites 68 and 156, respectively). As a part of a multi-molecular complex, it is involved in a non-homologous reduction of DNA double-strand breaks [ 105 , 106 ]. Such temporary breaks occur under the influence of another AIRE partner DNA-Top IIα, which relaxes supercoils in the transcription start sites (TSSs) of TSAs and simplifies the synthesis of their mRNA [ 61 , 107 ].…”

Section: Molecular Mechanisms Of Aire Actionmentioning

confidence: 99%

Phylogeny, Structure, Functions, and Role of AIRE in the Formation of T-Cell Subsets

Shevyrev

Tereshchenko

Козлов

et al. 2022

Cells

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It is well known that the most important feature of adaptive immunity is the specificity that provides highly precise recognition of the self, altered-self, and non-self. Due to the high specificity of antigen recognition, the adaptive immune system participates in the maintenance of genetic homeostasis, supports multicellularity, and protects an organism from different pathogens at a qualitatively different level than innate immunity. This seemingly simple property is based on millions of years of evolution that led to the formation of diversification mechanisms of antigen-recognizing receptors and later to the emergence of a system of presentation of the self and non-self antigens. The latter could have a crucial significance because the presentation of nearly complete diversity of auto-antigens in the thymus allows for the “calibration” of the forming repertoires of T-cells for the recognition of self, altered-self, and non-self antigens that are presented on the periphery. The central role in this process belongs to promiscuous gene expression by the thymic epithelial cells that express nearly the whole spectrum of proteins encoded in the genome, meanwhile maintaining their cellular identity. This complex mechanism requires strict control that is executed by several transcription factors. One of the most important of them is AIRE. This noncanonical transcription factor not only regulates the processes of differentiation and expression of peripheral tissue-specific antigens in the thymic medullar epithelial cells but also controls intercellular interactions in the thymus. Besides, it participates in an increase in the diversity and transfer of presented antigens and thus influences the formation of repertoires of maturing thymocytes. Due to these complex effects, AIRE is also called a transcriptional regulator. In this review, we briefly described the history of AIRE discovery, its structure, functions, and role in the formation of antigen-recognizing receptor repertoires, along with other transcription factors. We focused on the phylogenetic prerequisites for the development of modern adaptive immunity and emphasized the importance of the antigen presentation system.

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Role of PRKDC in cancer initiation, progression, and treatment

Cited by 30 publications

References 68 publications

CRISPR-Cas9 Screen Identifies DYRK1A as a Target for Radiotherapy Sensitization in Pancreatic Cancer

CRISPR-Cas9 Screen Identifies DYRK1A as a Target for Radiotherapy Sensitization in Pancreatic Cancer

Evaluation of immunotherapy efficacy in gynecologic cancer

Phylogeny, Structure, Functions, and Role of AIRE in the Formation of T-Cell Subsets

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