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

DOI: 10.1126/sciadv.abc0629 DOI Help

Authors: Syed Feroj Ahmed (Cancer Research UK Beatson Institute) , Lori Buetow (Cancer Research UK Beatson Institute) , Mads Gabrielsen (University of Glasgow) , Sergio Lilla (Cancer Research UK Beatson Institute) , Chatrin Chatrin (Cancer Research UK Beatson Institute; University of Glasgow) , Gary J. Sibbet (Cancer Research UK Beatson Institute) , Sara Zanivan (Cancer Research UK Beatson Institute) , Danny Huang (Cancer Research UK Beatson Institute; University of Glasgow)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science Advances , VOL 6

State: Published (Approved)
Published: August 2020
Diamond Proposal Number(s): 16258

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography


Discipline Tags:

Life Sciences & Biotech Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)