PT  - JOURNAL ARTICLE
AU  - Guangai Xue
AU  - Klaudia Braczyk
AU  - Daniel Gonçalves-Carneiro
AU  - Daria M. Dawidziak
AU  - Katarzyna Zawada
AU  - Heley Ong
AU  - Yueping Wan
AU  - Kaneil K. Zadrozny
AU  - Barbie K. Ganser-Pornillos
AU  - Paul D. Bieniasz
AU  - Owen Pornillos
TI  - Poly(ADP-ribose) potentiates ZAP antiviral activity
AID  - 10.1101/2020.12.17.423219
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.12.17.423219
4099  - http://biorxiv.org/content/early/2020/12/17/2020.12.17.423219.short
4100  - http://biorxiv.org/content/early/2020/12/17/2020.12.17.423219.full
AB  - Zinc-finger antiviral protein (ZAP), also known as poly(ADP-ribose) polymerase 13 (PARP13), is an antiviral factor that selectively targets viral RNA for degradation. ZAP is active against both DNA and RNA viruses, including important human pathogens such as hepatitis B virus and type 1 human immunodeficiency virus (HIV-1). ZAP selectively binds CpG dinucleotides through its N-terminal RNA-binding domain, which consists of four zinc fingers. ZAP also contains a central region that consists of a fifth zinc finger and two WWE domains. Through structural and biochemical studies, we found that the fifth zinc finger and tandem WWEs of ZAP combine into a single integrated domain that binds to poly(ADP-ribose) (PAR), a cellular polynucleotide. PAR binding is mediated by the second WWE module of ZAP and likely involves specific recognition of iso(ADP-ribose), a repeating structural unit of PAR. Mutation of the putative iso(ADP-ribose) binding site in ZAP abrogates the interaction in vitro and diminishes ZAP activity against a CpG-rich HIV-1 reporter virus. In cells, PAR facilitates formation of non-membranous sub-cellular compartments such as DNA repair foci, spindle poles and cytosolic RNA stress granules. Our results suggest that ZAP-mediated viral mRNA degradation is facilitated by PAR, and provides a biophysical rationale for the reported association of ZAP with RNA stress granules.