Specificity of DNA ADP-Ribosylation Reversal by NADARs

Cihlova, Bara; Lu, Yang; Mikoč, Andreja; Schuller, Marion; Ahel, Ivan (2024) Specificity of DNA ADP-Ribosylation Reversal by NADARs. Toxins, 16 (5). ISSN 2072-6651

PDF - Published Version - article Available under License Creative Commons Attribution. Download (4MB)

Abstract

Recent discoveries establish DNA and RNA as bona fide substrates for ADP-ribosylation. NADAR (“NAD- and ADP-ribose”-associated) enzymes reverse guanine ADP-ribosylation and serve as antitoxins in the DarT-NADAR operon. Although NADARs are widespread across prokaryotes, eukaryotes, and viruses, their specificity and broader physiological roles remain poorly understood. Using phylogenetic and biochemical analyses, we further explore de-ADP-ribosylation activity and antitoxin functions of NADAR domains. We demonstrate that different subfamilies of NADAR proteins from representative E. coli strains and an E. coli-infecting phage retain biochemical activity while displaying specificity in providing protection from toxic guanine ADP-ribosylation in cells. Furthermore, we identify a myxobacterial enzyme within the YbiA subfamily that functions as an antitoxin for its associated DarT-unrelated ART toxin, which we termed YarT, thus presenting a hitherto uncharacterised ART-YbiA toxin–antitoxin pair. Our studies contribute to the burgeoning field of DNA ADP-ribosylation, supporting its physiological relevance within and beyond bacterial toxin–antitoxin systems. Notably, the specificity and confinement of NADARs to non-mammals infer their potential as highly specific targets for antimicrobial drugs with minimal off-target effects.

Item Type:	Article
Uncontrolled Keywords:	ADP-ribosylation; toxin–antitoxin system; DNA modification; PARP; DNA damage; YbiA; DarTG
Subjects:	NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions:	Division of Molecular Biology
Depositing User:	Ivana Vuglec
Date Deposited:	13 Oct 2025 08:54
URI:	http://fulir.irb.hr/id/eprint/10004
DOI:	10.3390/toxins16050208

Actions (login required)

View Item