1Section of Hematology/Oncology, Department of Medicine.
2Section of Hematology/Oncology, Department of Medicine,Integrative Molecular and Biomedical Sciences Graduate Program.
3Section of Hematology/Oncology, Department of Medicine,Interdepartmental Program in Translational Biology and Molecular Medicine.
4Section of Hematology/Oncology, Department of Medicine,Integrative Molecular and Biomedical Sciences Graduate Program,Interdepartmental Program in Translational Biology and Molecular Medicine,Department of Molecular and Cellular Biology, andDan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030 [email protected]
Several ring between ring fingers (RBR) -domain proteins, such as Parkin and Parc, have been shown to be E3 ligases involved in important biological processes. Here, we identify a poorly characterized RBR protein, Ring Finger protein 144A (RNF144A), as the first, to our knowledge, mammalian E3 ubiquitin ligase for DNA-PKcs. We show that DNA damage induces RNF144A expression in a p53-dependent manner. RNF144A is mainly localized in the cytoplasmic vesicles and plasma membrane and interacts with cytoplasmic DNA-dependent protein kinase, catalytic subunit (DNA-PKcs). DNA-PKcs plays a critical role in the nonhomologous end-joining DNA repair pathway and provides prosurvival signaling during DNA damage. We show that RNF144A induces ubiquitination of DNA-PKcs in vitro and in vivo and promotes its degradation. Depletion of RNF144A leads to an increased level of DNA-PKcs and resistance to DNA damaging agents, which is reversed by a DNA-PK inhibitor. Taken together, our data suggest that RNF144A may be involved in p53-mediated apoptosis through down-regulation of DNA-PKcs when cells suffer from persistent or severe DNA damage insults.
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This record was last updated on 01/13/2018 and may not reflect the most current and accurate biomedical/scientific data available from NLM.
The corresponding record at NLM can be accessed at https://www.ncbi.nlm.nih.gov/pubmed/24979766