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

Xiao Wu, Shichang Liu, Cari Sagum, Jianji Chen, Rajesh Singh, Apurva Chaturvedi, John R. Horton, Tanuja R. Kashyap, David Fushman, Xiaodong Cheng, Mark T. Bedford, Bin Wang

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The establishment of polyubiquitin conjugates with distinct linkages play important roles in the DNA damage response. Much remains unknown about the regulation of linkage-specific ubiquitin signaling at sites of DNA damage. Here we reveal that Cezanne (also known as Otud7B) deubiquitinating enzyme promotes the recruitment of Rap80/BRCA1-A complex by binding to Lys63-polyubiquitin and targeting Lys11-polyubiquitin. Using a ubiquitin binding domain protein array screen, we identify that the UBA domains of Cezanne and Cezanne2 (also known as Otud7A) selectively bind to Lys63-linked polyubiquitin. Increased Lys11-linkage ubiquitination due to lack of Cezanne DUB activity compromises the recruitment of Rap80/BRCA1-A. Cezanne2 interacts with Cezanne, facilitating Cezanne in the recruitment of Rap80/BRCA1-A, Rad18, and 53BP1, in cellular resistance to ionizing radiation and DNA repair. Our work presents a model that Cezanne serves as a "reader" of the Lys63-linkage polyubiquitin at DNA damage sites and an "eraser" of the Lys11-linkage ubiquitination, indicating a crosstalk between linkage-specific ubiquitination at DNA damage sites.

Original languageEnglish (US)
Pages (from-to)1702-1717
Number of pages16
JournalGenes & development
Volume33
Issue number23-24
DOIs
StatePublished - Dec 1 2019

Keywords

  • 53BP1
  • Abraxas
  • BRCA1
  • Cezanne
  • DNA damage response
  • DNA double-strand breaks
  • DUB
  • Lys11-linkage ubiquitin
  • Lys63-linkage ubiquitin
  • Rap80

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

MD Anderson CCSG core facilities

  • Functional Genomics Core
  • Protein Array and Analysis Core

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