Crosstalk between Lys63- and Lys11-polyubiquitin signaling at DNA damage sites is driven by Cezanne
- Xiao Wu1,
- Shichang Liu1,
- Cari Sagum2,
- Jianji Chen2,
- Rajesh Singh3,
- Apurva Chaturvedi3,
- John R. Horton2,
- Tanuja R. Kashyap4,
- David Fushman4,
- Xiaodong Cheng2,
- Mark T. Bedford2 and
- Bin Wang1,5
- 1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
- 2Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
- 3LifeSensors, Malvern, Pennsylvania 19355, USA;
- 4Department of Chemistry & Biochemistry, University of Maryland, College Park, Maryland 20742, USA;
- 5Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, Texas 77030, USA
- Corresponding authors: mtbedford{at}mdanderson.org, bwang3{at}mdanderson.org
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.
Keywords
- 53BP1
- Abraxas
- BRCA1
- Cezanne
- DNA damage response
- DNA double-strand breaks
- DUB
- Lys11-linkage ubiquitin
- Lys63-linkage ubiquitin
- Rap80
Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.332395.119.
- Received September 4, 2019.
- Accepted October 16, 2019.
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