Abstract
Cullin 4 (CUL4) and small ring finger protein ROC1 assemble to form E3 ubiquitin ligase (CRL4) complexes. CUL4 interacts with WD-40 proteins through the adaptor protein DNA damage-binding protein 1 (DDB1) to target substrates for ubiquitylation. Very little is known on how the CUL4 and DDB1 interaction is regulated. Here, we show that DDB1 is acetylated and acetylation promotes DDB1 binding to CUL4. We also identify nucleolar sirtuin 7 (SIRT7) as a major deacetylase that negatively regulates DDB1-CUL4 interaction. Following inhibition of nucleolar function by actinomycin D or 5-fluorouracil treatment or knocking down the gene for the RNA polymerase I component UBF, SIRT7 is mobilized from the nucleolus to the nucleoplasm and promotes DDB1 deacetylation, leading to decreased DDB1-CUL4 association and CRL4 activity. This results in the accumulation or activation of CRL4 substrates including LATS1 and p73, which contribute to cell apoptosis induced by actinomycin D and 5-fluorouracil. Our study uncovers a novel regulation of CRL4 E3 ligase complexes.