Deltex family E3 ligases specifically ubiquitinate the terminal ADP-ribose of poly(ADP-ribosyl)ation

• Published in: Biochemical and biophysical research communications 2024-08, Vol.720, p.150101-150101, Article 150101
• Main Authors: Kelly, Matthew, Dietz, Chase, Kasson, Samuel, Zhang, Yong, Holtzman, Michael J., Kim, In-Kwon
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate Ribose - metabolism; ADP-Ribosylation; HEK293 Cells; Humans; Poly Adenosine Diphosphate Ribose - metabolism; Poly ADP Ribosylation; Poly(ADP-ribose) Polymerases - chemistry; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.150101

Poly(ADP-ribose) polymerases (PARPs) are critical to regulating cellular activities, such as the response to DNA damage and cell death. PARPs catalyze a reversible post-translational modification (PTM) in the form of mono- or poly(ADP-ribosyl)ation. This type of modification is known to form a ubiquitin-ADP-ribose (Ub-ADPR) conjugate that depends on the actions of Deltex family of E3 ubiquitin ligases (DTXs). In particular, DTXs add ubiquitin to the 3′-OH of adenosine ribose′ in ADP-ribose, which effectively sequesters ubiquitin and impedes ubiquitin-dependent signaling. Previous work demonstrates DTX function for ubiquitination of protein-free ADPR, mono-ADP-ribosylated peptides, and ADP-ribosylated nucleic acids. However, the dynamics of DTX-mediated ubiquitination of poly(ADP-ribosyl)ation remains to be defined. Here we show that the ADPR ubiquitination function is not found in other PAR-binding E3 ligases and is conserved across DTX family members. Importantly, DTXs specifically target poly(ADP-ribose) chains for ubiquitination that can be cleaved by PARG, the primary eraser of poly(ADP-ribose), leaving the adenosine-terminal ADPR unit conjugated to ubiquitin. Our collective results demonstrate the DTXs’ specific ubiquitination of the adenosine terminus of poly(ADP-ribosyl)ation and suggest the unique Ub-ADPR conjugation process as a basis for PARP-DTX control of cellular activities. •Deltex E3 ligases ubiquitinate the adenosine terminus of poly(ADP-ribosyl)ation.•Ubiquitin-poly(ADP-ribose) conjugates are processed by PARG, leaving the terminal ADP-ribose conjugated to ubiquitin.•The ADP-ribose ubiquitination function is unique in Deltex E3 ligases, not found in other ADP-ribose-binding E3 ligases.