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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates

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

Yan Mo1, Ran Lin1, Peng Liu1

  • 1The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Research Lab of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

The FEBS Journal
|September 9, 2017
PubMed

Insights

Acetylation of DNA damage-binding protein 1 (DDB1) enhances its binding to Cullin 4 (CUL4), forming E3 ligase complexes. Nucleolar sirtuin 7 (SIRT7) deacetylates DDB1, reducing CRL4 activity and promoting apoptosis.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cullin 4 (CUL4) and ROC1 form E3 ubiquitin ligase (CRL4) complexes.
  • CUL4-DDB1 interaction targets substrates for ubiquitylation, but its regulation is poorly understood.

Purpose of the Study:

  • To investigate the regulation of the DDB1-CUL4 interaction.
  • To identify factors influencing CRL4 E3 ligase complex activity.

Main Methods:

  • Demonstrated DDB1 acetylation and its effect on CUL4 binding.
  • Identified SIRT7 as a DDB1 deacetylase.
  • Observed SIRT7 mobilization and DDB1 deacetylation upon nucleolar stress (actinomycin D, 5-fluorouracil, UBF knockdown).

Main Results:

  • Acetylation promotes DDB1 binding to CUL4.
  • SIRT7 deacetylates DDB1, decreasing DDB1-CUL4 association and CRL4 activity.
  • Nucleolar stress induces SIRT7 relocation, leading to DDB1 deacetylation and CRL4 inhibition.
  • CRL4 substrate accumulation (LATS1, p73) contributes to apoptosis.

Conclusions:

  • Uncovered a novel regulatory mechanism for CRL4 E3 ligase complexes involving DDB1 acetylation and SIRT7.
  • Demonstrated the role of nucleolar function and SIRT7 in controlling CRL4 activity and substrate levels.
  • Linked CRL4 regulation to apoptosis induction by specific treatments.
Keywords:
CRL4 E3 ligaseDDB1SIRT7acetylationnucleolar function inhibition

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