ArticleNucleic acids research2021
Ablating putative Ku70 phosphorylation sites results in defective DNA damage repair and spontaneous induction of hepatocellular carcinoma.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 19 citations in OpenAlex.
- Nuclear VPS35 attenuates NHEJ repair by sequestering Ku protein.Molecular medicine (Cambridge, Mass.) · 2025Article
- Redox regulation: mechanisms, biology and therapeutic targets in diseases.Signal transduction and targeted therapy · 2025Review
- Defective homologous recombination and genomic instability predict increased responsiveness to carbon ion radiotherapy in pancreatic cancer.NPJ precision oncology · 2025Article
- Satellite cell-derived TRIM28 is pivotal for mechanical load- and injury-induced myogenesis.EMBO reports · 2024Article
- Interactions between the DNA Damage Response and the Telomere Complex in Carcinogenesis: A Hypothesis.Current issues in molecular biology · 2023Review
- ATM phosphorylates the FATC domain of DNA-PKcs at threonine 4102 to promote non-homologous end joining.Nucleic acids research · 2023Article
- A novel NHEJ gene signature based model for risk stratification and prognosis prediction in hepatocellular carcinoma.Cancer cell international · 2023Article
- A Simple CRISPR/Cas9 System for Efficiently Targeting Genes of Aspergillus SectionMicrobiology spectrum · 2023Article
- DNA-PKcs-dependent phosphorylation of RECQL4 promotes NHEJ by stabilizing the NHEJ machinery at DNA double-strand breaks.Nucleic acids research · 2022Article
- Acox2 is a regulator of lysine crotonylation that mediates hepatic metabolic homeostasis in mice.Cell death & disease · 2022Article
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Authors and funding
7 authors at 2 institutions in 1 country.
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Abstract
Multiple pathways mediate the repair of DNA double-strand breaks (DSBs), with numerous mechanisms responsible for driving choice between the pathways. Previously, we reported that mutating five putative phosphorylation sites on the non-homologous end joining (NHEJ) factor, Ku70, results in sustained retention of human Ku70/80 at DSB ends and attenuation of DSB repair via homologous recombination (HR). In this study, we generated a knock-in mouse, in which the three conserved putative phosphorylation sites of Ku70 were mutated to alanine to ablate potential phosphorylation (Ku703A/3A), in order to examine if disrupting DSB repair pathway choice by modulating Ku70/80 dynamics at DSB ends results in enhanced genomic instability and tumorigenesis. The Ku703A/3A mice developed spontaneous and have accelerated chemical-induced hepatocellular carcinoma (HCC) compared to wild-type (Ku70+/+) littermates. The HCC tumors from the Ku703A/3A mice have increased γH2AX and 8-oxo-G staining, suggesting decreased DNA repair. Spontaneous transformed cell lines from Ku703A/3A mice are more radiosensitive, have a significant decrease in DNA end resection, and are more sensitive to the DNA cross-linking agent mitomycin C compared to cells from Ku70+/+ littermates. Collectively, these findings demonstrate that mutating the putative Ku70 phosphorylation sites results in defective DNA damage repair and disruption of this process drives genomic instability and accelerated development of HCC.
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