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Structural basis for DNA break recognition by ARTD2/PARP2

DOI: 10.1093/nar/gky927 DOI Help

Authors: Ezeogo Obaji (University of Oulu) , Teemu Haikarainen (University of Oulu) , Lari Lehtiö (University of Oulu)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nucleic Acids Research , VOL 7

State: Published (Approved)
Published: October 2018
Diamond Proposal Number(s): 14794

Open Access Open Access

Abstract: Human ARTD2 (or PARP2) is an ADP-ribosyltransferase, which is catalytically activated by binding to damaged DNA. ARTD2 subsequently ADP-ribosylates itself and other proteins, initiating a cascade of events leading to DNA repair. In contrast to ARTD1, the founding member of the enzyme family, ARTD2 does not have specialized zinc-fingers for detecting DNA damage. The domain organization of ARTD2 includes disordered N-terminus, WGR and catalytic domains. However, the N-terminus of ARTD2 is not strictly required for the DNA dependent activity. While it is known that ARTD2 requires the WGR domain for efficient DNA binding and subsequent catalytic activation, the mechanism of DNA damage detection and subsequent catalytic activation are not completely understood. Here, we report crystal structures of ARTD2 WGR domain bound to double-strand break mimicking DNA oligonucleotides. Notably, the crystal structures revealed DNA binding mode of ARTD2 involving DNA end to end interaction. Structures demonstrate how ARTD2 recognizes nicked DNA, how it interacts with the 5′-phosphate group, and how it can mediate joining of DNA ends in vitro. Extensive mutagenesis of the ARTD2-DNA interface combined with activity, binding, and stoichiometry measurements demonstrate that the WGR domain is the key for DNA break detection.

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 01/11/2018 08:59

Discipline Tags:

Biochemistry Catalysis Chemistry Structural biology Biophysics Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)