Lysines 3241 and 3260 of DNA-PKcs are important for genomic stability and radioresistance

Mori, Eiichiro; Davis, Anthony J.; Hasegawa, Masatoshi; Chen, David J.

doi:10.1016/j.bbrc.2016.06.048

Cited by 13 publications

(8 citation statements)

References 47 publications

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“…Instead, in the absence of p300, DNA-PKcs repair complexes become more persistent. DNA-PKcs activity requires acetylation, but the histone acetyltransferase was not determined [ 71 ]. Perhaps p300 is responsible for the post-translational modification.…”

Section: Discussionmentioning

confidence: 99%

Beta Human Papillomavirus 8E6 Attenuates Non-Homologous End Joining by Hindering DNA-PKcs Activity

Bugbee

Gamez

et al. 2020

Cancers

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Cutaneous viral infections occur in a background of near continual exposure to environmental genotoxins, like UV radiation in sunlight. Failure to repair damaged DNA is an established driver of tumorigenesis and substantial cellular resources are devoted to repairing DNA lesions. Beta-human papillomaviruses (β-HPVs) attenuate DNA repair signaling. However, their role in human disease is unclear. Some have proposed that β-HPV promotes tumorigenesis, while others suggest that β-HPV protects against skin cancer. Most of the molecular evidence that β-HPV impairs DNA repair has been gained via characterization of the E6 protein from β-HPV 8 (β-HPV 8E6). Moreover, β-HPV 8E6 hinders DNA repair by binding and destabilizing p300, a transcription factor for multiple DNA repair genes. By reducing p300 availability, β-HPV 8E6 attenuates a major double strand DNA break (DSB) repair pathway, homologous recombination. Here, β-HPV 8E6 impairs another DSB repair pathway, non-homologous end joining (NHEJ). Specifically, β-HPV 8E6 acts by attenuating DNA-dependent protein kinase (DNA-PK) activity, a critical NHEJ kinase. This includes DNA-PK activation and the downstream of steps in the pathway associated with DNA-PK activity. Notably, β-HPV 8E6 inhibits NHEJ through p300 dependent and independent means. Together, these data expand the known genome destabilizing capabilities of β-HPV 8E6.

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Section: Discussionmentioning

confidence: 99%

Beta Human Papillomavirus 8E6 Attenuates Non-Homologous End Joining by Hindering DNA-PKcs Activity

Bugbee

Gamez

et al. 2020

Cancers

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“…Deacetylation of DNA-PKcs (Lys3241 and Lys3260) in vivo has been confirmed to decrease the capacity of DSBs and increase the radiosensitivity of Chinese hamster ovary cells. However, which HAT catalyzed the acetylation of DNA-PKcs needs further validation (99). As a docking site for other c-NHEJ proteins, Ku70/80 heterodimer was known to interact with the LIG4-XRCC4-XLF complex, which plays an essential role in DNA end bridging and ligation (100,101).…”

Section: Non-homologous End Joiningmentioning

confidence: 99%

Acetylation and Deacetylation of DNA Repair Proteins in Cancers

Shi

Liu

et al. 2020

Front. Oncol.

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Hundreds of DNA repair proteins coordinate together to remove the diverse damages for ensuring the genomic integrity and stability. The repair system is an extensive network mainly encompassing cell cycle arrest, chromatin remodeling, various repair pathways, and new DNA fragment synthesis. Acetylation on DNA repair proteins is a dynamic epigenetic modification orchestrated by lysine acetyltransferases (HATs) and lysine deacetylases (HDACs), which dramatically affects the protein functions through multiple mechanisms, such as regulation of DNA binding ability, protein activity, post-translational modification (PTM) crosstalk, and protein-protein interaction. Accumulating evidence has indicated that the aberrant acetylation of DNA repair proteins contributes to the dysfunction of DNA repair ability, the pathogenesis and progress of cancer, as well as the chemosensitivity of cancer cells. In the present scenario, targeting epigenetic therapy is being considered as a promising method at par with the conventional cancer therapeutic strategies. This present article provides an overview of the recent progress in the functions and mechanisms of acetylation on DNA repair proteins involved in five major repair pathways, which warrants the possibility of regulating acetylation on repair proteins as a therapeutic target in cancers.

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“…In this way we avoid confounding factors due to other cell cycle effects (such as Homologous Recombination). Time constants in the models, which govern the recruitment of repair proteins to DSB ends, are fitted to reproduce in vitro experiments from literature with cells irradiated by lasers [ 40 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ]. We have discussed the suitability of applying laser induced damage repair kinetics to ionising radiation in previous work [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

Mechanistic Modelling of Slow and Fast NHEJ DNA Repair Pathways Following Radiation for G0/G1 Normal Tissue Cells

Warmenhoven

Henthorn

et al. 2021

Cancers

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Mechanistic in silico models can provide insight into biological mechanisms and highlight uncertainties for experimental investigation. Radiation-induced double-strand breaks (DSBs) are known to be toxic lesions if not repaired correctly. Non-homologous end joining (NHEJ) is the major DSB-repair pathway available throughout the cell cycle and, recently, has been hypothesised to consist of a fast and slow component in G0/G1. The slow component has been shown to be resection-dependent, requiring the nuclease Artemis to function. However, the pathway is not yet fully understood. This study compares two hypothesised models, simulating the action of individual repair proteins on DSB ends in a step-by-step manner, enabling the modelling of both wild-type and protein-deficient cell systems. Performance is benchmarked against experimental data from 21 cell lines and 18 radiation qualities. A model where resection-dependent and independent pathways are entirely separated can only reproduce experimental repair kinetics with additional restraints on end motion and protein recruitment. However, a model where the pathways are entwined was found to effectively fit without needing additional mechanisms. It has been shown that DaMaRiS is a useful tool when analysing the connections between resection-dependent and independent NHEJ repair pathways and robustly matches with experimental results from several sources.

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Lysines 3241 and 3260 of DNA-PKcs are important for genomic stability and radioresistance

Cited by 13 publications

References 47 publications

Beta Human Papillomavirus 8E6 Attenuates Non-Homologous End Joining by Hindering DNA-PKcs Activity

Beta Human Papillomavirus 8E6 Attenuates Non-Homologous End Joining by Hindering DNA-PKcs Activity

Acetylation and Deacetylation of DNA Repair Proteins in Cancers

Mechanistic Modelling of Slow and Fast NHEJ DNA Repair Pathways Following Radiation for G0/G1 Normal Tissue Cells

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