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Structural insights into two distinct binding modules for Lys63-linked polyubiquitin chains in RNF168

Tomio S Takahashi1,2, Yoshihiro Hirade3, Aya Toma1,2,4

  • 1Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan.

Nature Communications
|January 14, 2018
PubMed

Insights

The E3 ubiquitin ligase RNF168 is crucial for DNA damage repair. Structural studies reveal how RNF168 binds to ubiquitylated targets, with the UDM2 region being key for its recruitment to double-strand break sites.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Structural Biology

Background:

  • RNF168 is an E3 ubiquitin ligase essential for the DNA damage response.
  • RNF168 recruitment to double-strand breaks (DSBs) depends on ubiquitylated targets via its UDM1 and UDM2 regions.

Purpose of the Study:

  • To elucidate the structural basis of RNF168's interaction with Lys63-linked ubiquitin chains.
  • To determine the distinct roles of UDM1 and UDM2 in RNF168 recruitment to DSBs.

Main Methods:

  • X-ray crystallography to determine the structures of UDM1-diUb and UDM2ΔC-diUb complexes.
  • Biochemical assays to analyze ubiquitin-binding mechanisms.
  • Site-directed mutagenesis in U2OS cells to assess RNF168 recruitment to DSBs.

Main Results:

  • Crystal structures reveal UDM1 and UDM2ΔC as α-helices binding to Lys63-linked diubiquitin (K63-Ub2).
  • Specific binding to distal and proximal ubiquitin moieties confers specificity for Lys63-linked chains.
  • Mutations in UDM2, but not UDM1, significantly impair RNF168 accumulation at DSB sites.

Conclusions:

  • RNF168 utilizes distinct ubiquitin-binding modules (UDM1 and UDM2) for target recognition.
  • UDM2 plays a primary role in recruiting RNF168 to DNA damage sites through interactions with ubiquitylated targets.

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