title: RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage.
abstract: 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.
authors: Section of Hematology/Oncology, Department of Medicine.
authors: Shiuh-Rong
authors: SR
authors: Ho
authors: Section of Hematology/Oncology, Department of Medicine,Integrative Molecular and Biomedical Sciences Graduate Program.
authors: Christina S
authors: CS
authors: Mahanic
authors: Section of Hematology/Oncology, Department of Medicine,Interdepartmental Program in Translational Biology and Molecular Medicine.
authors: Yu-Ju
authors: YJ
authors: Lee
authors: Section 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 weeichil@bcm.edu.
authors: Weei-Chin
authors: WC
authors: Lin
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D020134:Catalytic Domain / Q000502:physiology*; D003114:Colony-Forming Units Assay; D004249:DNA Damage / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D051747:DNA-Activated Protein Kinase / Q000378:metabolism / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; C571196:RNF144A protein, human; D044767:Ubiquitin-Protein Ligases; D051747:DNA-Activated Protein Kinase
keywords: DDR; endosome; transmembrane domain