DELTEX2 C-terminal domain recognizes and recruits ADP-ribosylated proteins for ubiquitination

Ahmed, S. F., Buetow, L., Gabrielsen, M. , Lilla, S., Chatrin, C., Sibbet, G. J., Zanivan, S. and Huang, D. T. (2020) DELTEX2 C-terminal domain recognizes and recruits ADP-ribosylated proteins for ubiquitination. Science Advances, 6(34), eabc0629. (doi: 10.1126/sciadv.abc0629) (PMID:32937373) (PMCID:PMC7442474)

Abstract

Cross-talk between ubiquitination and ADP-ribosylation regulates spatiotemporal recruitment of key players in many signaling pathways. The DELTEX family ubiquitin ligases (DTX1 to DTX4 and DTX3L) are characterized by a RING domain followed by a C-terminal domain (DTC) of hitherto unknown function. Here, we use two label-free mass spectrometry techniques to investigate the interactome and ubiquitinated substrates of human DTX2 and identify a large proportion of proteins associated with the DNA damage repair pathway. We show that DTX2-catalyzed ubiquitination of these interacting proteins requires PARP1/2-mediated ADP-ribosylation and depends on the DTC domain. Using a combination of structural, biochemical, and cell-based techniques, we show that the DTX2 DTC domain harbors an ADP-ribose–binding pocket and recruits poly-ADP-ribose (PAR)–modified proteins for ubiquitination. This PAR-binding property of DTC domain is conserved across the DELTEX family E3s. These findings uncover a new ADP-ribose–binding domain that facilitates PAR-dependent ubiquitination.

• Item Type: Articles
• Additional Information: Funding: This work was supported by Cancer Research UK (A23278 to D.T.H. and A29800 to S.Z.) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 647849 to D.T.H.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Chatrin, Chatrin and Lilla, Dr Sergio and Huang, Professor Danny and Gabrielsen, Dr Mads and Sibbet, Dr Gary and Zanivan, Professor Sara and Buetow, Dr Lori
• Authors: Ahmed, S. F., Buetow, L., Gabrielsen, M., Lilla, S., Chatrin, C., Sibbet, G. J., Zanivan, S., and Huang, D. T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Science Advances
• Publisher: American Association for the Advancement of Science
• ISSN: 2375-2548
• ISSN (Online): 2375-2548
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Science Advances 6(34):eabc0629
• Publisher Policy: Reproduced under a Creative Commons license