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 language | English (US) |
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Pages (from-to) | 1702-1717 |
Number of pages | 16 |
Journal | Genes & development |
Volume | 33 |
Issue number | 23-24 |
DOIs | |
State | Published - 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