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The multifaceted functions of DNA-PKcs: implications for the therapy of human diseases
Jinghong Wu1, Liwei Song2, Mingjun Lu1
1Cancer Research Center Beijing Chest Hospital Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute Beijing China.
Abstract:
The DNA-dependent protein kinase (DNA-PK), catalytic subunit, also known as DNA-PKcs, is complexed with the heterodimer Ku70/Ku80 to form DNA-PK holoenzyme, which is well recognized as initiator in the nonhomologous end joining (NHEJ) repair after double strand break (DSB). During NHEJ, DNA-PKcs is essential for both DNA end processing and end joining. Besides its classical function in DSB repair, DNA-PKcs also shows multifaceted functions in various biological activities such as class switch recombination (CSR) and variable (V) diversity (D) joining (J) recombination in B/T lymphocytes development, innate immunity through cGAS-STING pathway, transcription, alternative splicing, and so on, which are dependent on its function in NHEJ or not. Moreover, DNA-PKcs deficiency has been proven to be related with human diseases such as neurological pathogenesis, cancer, immunological disorder, and so on through different mechanisms. Therefore, it is imperative to summarize the latest findings about DNA-PKcs and diseases for better targeting DNA-PKcs, which have shown efficacy in cancer treatment in preclinical models. Here, we discuss the multifaceted roles of DNA-PKcs in human diseases, meanwhile, we discuss the progresses of DNA-PKcs inhibitors and their potential in clinical trials. The most updated review about DNA-PKcs will hopefully provide insights and ideas to understand DNA-PKcs associated diseases.
Insights
DNA-dependent protein kinase (DNA-PKcs) is crucial for DNA repair and has diverse roles in immunity and development. Understanding DNA-PKcs
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- DNA-dependent protein kinase (DNA-PK), catalytic subunit (DNA-PKcs), forms the DNA-PK holoenzyme with Ku70/Ku80.
- This holoenzyme initiates nonhomologous end joining (NHEJ) for DNA double-strand break (DSB) repair.
- DNA-PKcs is vital for DNA end processing and joining during NHEJ.
Purpose of the Study:
- To review the multifaceted roles of DNA-PKcs in human diseases.
- To discuss the therapeutic potential of DNA-PKcs inhibitors in clinical trials.
- To provide insights into DNA-PKcs-associated diseases.
Main Methods:
- Literature review of DNA-PKcs functions and disease associations.
- Analysis of preclinical data on DNA-PKcs inhibitors in cancer treatment.
- Discussion of current progress in clinical trials for DNA-PKcs inhibitors.
Main Results:
- DNA-PKcs has diverse functions beyond DSB repair, including roles in V(D)J recombination, class switch recombination (CSR), and innate immunity.
- DNA-PKcs deficiency is linked to neurological, cancer, and immunological disorders.
- DNA-PKcs inhibitors show promise in preclinical cancer models.
Conclusions:
- DNA-PKcs plays a critical role in maintaining genomic stability and has broader biological functions.
- Targeting DNA-PKcs presents a promising therapeutic strategy for various diseases, particularly cancer.
- Further research into DNA-PKcs inhibitors is warranted for clinical application.
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