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Crosstalk between Lys63- and Lys11-polyubiquitin signaling at DNA damage sites is driven by Cezanne

Xiao Wu1, Shichang Liu1, Cari Sagum2

  • 1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Genes & Development
|November 9, 2019
PubMed

Insights

Cezanne deubiquitinating enzyme reads Lys63-linked ubiquitin and erases Lys11-linked ubiquitin at DNA damage sites. This dual function is crucial for recruiting DNA repair complexes like Rap80/BRCA1-A, aiding cellular resistance to radiation.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cellular Biology

Background:

  • Polyubiquitin chains with different linkages are critical for DNA damage response.
  • Regulation of linkage-specific ubiquitin signaling at DNA damage sites is not well understood.

Purpose of the Study:

  • To investigate the role of Cezanne (Otud7B) deubiquitinating enzyme in DNA damage response.
  • To elucidate the mechanism by which Cezanne regulates linkage-specific ubiquitination at DNA damage sites.

Main Methods:

  • Ubiquitin binding domain protein array screen to identify ubiquitin linkage specificities.
  • Assays to assess recruitment of DNA repair proteins (Rap80/BRCA1-A, Rad18, 53BP1).
  • Analysis of cellular resistance to ionizing radiation.

Main Results:

  • Cezanne and Cezanne2 selectively bind Lys63-linked polyubiquitin via their UBA domains.
  • Cezanne targets Lys11-linked polyubiquitin, and its DUB activity is essential for Rap80/BRCA1-A recruitment.
  • Cezanne2 interacts with Cezanne, enhancing the recruitment of repair factors and improving radiation resistance.

Conclusions:

  • Cezanne acts as a 'reader' of Lys63-ubiquitin and an 'eraser' of Lys11-ubiquitin at DNA damage sites.
  • This study reveals a crosstalk between distinct ubiquitin linkages in DNA repair.
  • Cezanne and Cezanne2 play vital roles in DNA repair pathways and cellular resistance to DNA damage.
Keywords:
53BP1AbraxasBRCA1CezanneDNA damage responseDNA double-strand breaksDUBLys11-linkage ubiquitinLys63-linkage ubiquitinRap80

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