MLH1 Deficiency-Triggered DNA Hyperexcision by Exonuclease 1 Activates the cGAS-STING Pathway

DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity

NEDDylation regulates RAD18 ubiquitination and localization in response to oxidative DNA damage

NEDDylation antagonizes ubiquitination of proliferating cell nuclear antigen and regulates the recruitment of polymerase η in response to oxidative DNA damage

The herpes simplex virus 1 UL36USP deubiquitinase suppresses DNA repair in host cells via deubiquitination of proliferating cell nuclear antigen

MyD88 NEDDylation negatively regulates MyD88-dependent NF-κB signaling through antagonizing its ubiquitination

RNF168-mediated H2A neddylation antagonizes its ubiquitination and regulates DNA damage repair

NEDD8 is an important regulatory factor in many biological processes. However, the substrates of neddylation and the relation between ubiquitin and NEDD8 pathways are remained largely unknown. Here, we showed that NEDD8 is covalently conjugated to H2A, and neddylation of H2A antagonizes its ubiquitination. NEDD8 suppresses H2A ubiquitination and decrease of the free NEDD8 level promotes H2A ubiquitination. We further found that E3 ligase RNF168 promotes both H2A ubiquitination and neddylation. Interestingly, RNF168 is a substrate of NEDD8 and neddylation of RNF168 is necessary for its E3 ubiquitin activity. Inhibition of RNF168 neddylation impairs the interaction between RNF168 and its E2 Ubc13. Moreover, in response to DNA damage, the level of H2A neddylation decreased with the increase of H2A ubiquitination, which facilitates DNA damage repair. And at the late stage of damage repair, H2A neddylation increased gradually while ubiquitination decreased to the basal levels. Mechanistically, NEDD8 negatively regulates DNA damage repair process by suppressing the ubiquitination of H2A and γH2AX, which further blocks the recruitment of damage-response protein BRCA1. Our findings elucidate the relation of H2A ubiquitination and neddylation, and suggest a novel modulate approach of DNA damage repair through neddylation pathway.

A CRM1-Dependent Nuclear Export Signal Controls Nucleocytoplasmic Translocation of HSCARG, Which Regulates NF-κB Activity