1. HUWE1-dependent DNA-PKcs neddylation modulates its autophosphorylation in DNA damage response.
- Author
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Guo Z, Wang S, Xie Y, Han Y, Hu S, Guan H, Xie D, Bai C, Liu X, Gu Y, Zhou PK, and Ma T
- Subjects
- Cell Line, DNA End-Joining Repair, DNA-Activated Protein Kinase chemistry, Humans, Phosphorylation, Phosphoserine metabolism, Protein Domains, DNA Damage, DNA-Activated Protein Kinase metabolism, NEDD8 Protein metabolism, Tumor Suppressor Proteins metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is the core component of DNA-PK complex in the non-homologous end-joining (NHEJ) repair of DNA double-strand breaks, and its activity is strictly controlled by DNA-PKcs phosphorylation. The ubiquitin-like protein, NEDD8 is involved in regulation of DNA damage response, but it remains mysterious whether and how NEDD8-related neddylation affects DNA-PKcs and the NHEJ process. Here, we show that DNA-PKcs is poly-neddylated at its kinase domain. The neddylation E2-conjugating enzyme UBE2M and E3 ligase HUWE1 (HECT, UBA, and WWE domain containing E3 ubiquitin protein ligase 1) are responsible for the DNA-PKcs neddylation. Moreover, inhibition of HUWE1-dependent DNA-PKcs neddylation impairs DNA-PKcs autophosphorylation at Ser2056. Finally, depletion of HUWE1-dependent DNA-PKcs neddylation reduces the efficiency of NHEJ. These studies provide insights how neddylation modulates the activity of NHEJ core complex.
- Published
- 2020
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