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RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage.

Authors
  • 1
  • 2
  • 3
  • 4
  • 1 Section of Hematology/Oncology, Department of Medicine.
  • 2 Section of Hematology/Oncology, Department of Medicine,Integrative Molecular and Biomedical Sciences Graduate Program.
  • 3 Section of Hematology/Oncology, Department of Medicine,Interdepartmental Program in Translational Biology and Molecular Medicine.
  • 4 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 [email protected]
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
1091-6490
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Volume
111
Issue
26
Identifiers
DOI: 10.1073/pnas.1323107111
PMID: 24979766
Source
Medline
Keywords
License
Unknown

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.

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