期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 26, 页码 E2646-E2655出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1323107111
关键词
endosome; DDR; transmembrane domain
资金
- National Institutes of Health [R01CA100857, R01CA138641, ARRA 3 P30CA125123-03S]
- Department of Defense Breast Cancer Research Program Grant [W81XWH-09-1-0338]
- T32 Fellowship [T32DK60445]
- Cancer Prevention and Research Institute of Texas Predoctoral Fellowship [CPRIT RP101499]
- Howard Hughes Medical Institute through the Med into Grad Initiative
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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