Details

Autor(en) / Beteiligte

• Mo, Yan
• Lin, Ran
• Liu, Peng
• Tan, Minjia
• Xiong, Yue
• Guan, Kun‐Liang
• Yuan, Hai‐Xin

Titel

SIRT7 deacetylates DDB1 and suppresses the activity of the CRL4 E3 ligase complexes

Ist Teil von

• The FEBS journal, 2017-11, Vol.284 (21), p.3619-3636

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2017

Link zum Volltext

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• 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. Interaction between cullin 4 (CUL4) and the adaptor protein DDB1 is critical for the activation of CRL4 E3 ligase, but its regulation is poorly understood. We found that, following inhibition of nucleolar function, sirtuin 7 (SIRT7) is mobilized from the nucleolus to the nucleoplasm and deacetylates DDB1, leading to decreased DDB1–CUL4 association and CRL4 activity. This results in accumulation or activation of CRL4 substrates involved in cell apoptosis.