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Molecular basis for the inhibition of the methyl-lysine binding function of 53BP1 by TIRR

Jiaxu Wang1, Zenglin Yuan2, Yaqi Cui1,3

  • 1College of Life Sciences, Hebei University, Baoding, 071000, Hebei, China.

Nature Communications
|July 14, 2018
PubMed

Insights

Tudor interacting repair regulator (TIRR) binds to 53BP1, blocking DNA repair. This structural study reveals how TIRR suppresses 53BP1’s role in DNA double-strand break repair, offering insights into DNA damage response pathways.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Genetics

Background:

  • 53BP1 is crucial for DNA double-strand break (DSB) repair.
  • Tudor interacting repair regulator (TIRR) negatively regulates 53BP1 during DSB repair.

Purpose of the Study:

  • To elucidate the molecular mechanism of TIRR-mediated suppression of 53BP1.
  • To determine the crystal structure of the 53BP1 tandem Tudor domain (TTD) in complex with TIRR.

Main Methods:

  • X-ray crystallography to determine the structure of the 53BP1 TTD-TIRR complex.
  • Site-directed mutagenesis to identify key interaction residues.
  • Biochemical assays to assess 53BP1 relocation and DNA repair activity.

Main Results:

  • The crystal structure reveals TIRR loops masking the 53BP1 TTD methylated lysine-binding pocket.
  • TIRR competes with histone H4K20 methylation for 53BP1 binding.
  • Mutations in key residues abolish 53BP1-TIRR complex formation, suppress 53BP1 relocation to DNA lesions, and inhibit 53BP1-dependent DNA repair.
  • NUDT16, despite homology, does not interact with 53BP1.

Conclusions:

  • TIRR directly binds to 53BP1 TTD, inhibiting its function in DNA repair.
  • The structural and functional data provide a molecular basis for TIRR's inhibitory role in DSB repair.
  • This study clarifies the mechanism of 53BP1 regulation by TIRR.

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