Family-wide analysis of human macrodomains reveals novel activities and identifies PARG as most efficient ADPr-RNA hydrolase

Communications Biology, vol. 8, pp. 453

Abstract

ADP-ribosylation is well-known as protein posttranslational modification and was recently also identified as RNA posttranscriptional modification. When macrodomain proteins were identified as protein ADP-ribosylhydrolases, several ADP-ribosylation substrates were not yet identified. Therefore, the majority of macrodomain-containing proteins have not been tested towards these additional substrates and were considered to be inactive. Here, we compare in vitro activities of the human macrodomains on a range of ADP-ribosylated substrates. We confirm recent findings that PARP9macro1 and PARP14macro1 can remove ADP-ribose from acidic residues and provide evidence that also PARP14macro2 and PARP15macro2 can function as ADP-ribosylhydrolases. In addition, we find that both PARP9macro1 and PARP14macro1 are active as ADPr-RNA decapping protein domains. Notwithstanding these in vitro activities, our data furthermore indicate that in HEK293 cells, PARG is the major ADPr-RNA decapping enzyme. Our findings thus expand the spectrum of known catalytic activities of human macrodomains and demonstrate their different efficiencies towards nucleic acid substrates.

Authors 10

1. Lisa Weixler Aachen Institute of Biochemistry and Molecular Biology

   RWTH Aachen University · University of Bonn · University Hospital Bonn

   Affiliation as printed

   Institute for Clinical Chemistry and Clinical Pharmacology, Venusberg-Campus 1, University Hospital Bonn, Bonn, Germany

   Institute of Biochemistry and Molecular Biology, Pauwelsstraße 30, RWTH Aachen University, Aachen, Germany

2. Roko Žaja corresponding Aachen Institute of Biochemistry and Molecular Biology

   RWTH Aachen University

   Affiliation as printed

   Institute of Biochemistry and Molecular Biology, Pauwelsstraße 30, RWTH Aachen University, Aachen, Germany. rzaja@ukaachen.de

   Institute of Biochemistry and Molecular Biology, Pauwelsstraße 30, RWTH Aachen University, Aachen, Germany

3. Nonso Josephat Ikenga Aachen Institute of Biochemistry and Molecular Biology

   RWTH Aachen University

   Affiliation as printed

   Institute of Biochemistry and Molecular Biology, Pauwelsstraße 30, RWTH Aachen University, Aachen, Germany

4. Jonas Siefert Aachen Institute of Biochemistry and Molecular Biology

   RWTH Aachen University

   Affiliation as printed

   Institute of Biochemistry and Molecular Biology, Pauwelsstraße 30, RWTH Aachen University, Aachen, Germany

5. Ganga Mohan Aachen Institute of Biochemistry and Molecular Biology

   RWTH Aachen University

   Affiliation as printed

   Institute of Biochemistry and Molecular Biology, Pauwelsstraße 30, RWTH Aachen University, Aachen, Germany

6. Gülcan Aydın Aachen Institute of Biochemistry and Molecular Biology

   RWTH Aachen University

   Affiliation as printed

   Institute of Biochemistry and Molecular Biology, Pauwelsstraße 30, RWTH Aachen University, Aachen, Germany

7. Sven Wijngaarden

   Leiden University

   Affiliation as printed

   Leiden Institute of Chemistry, Leiden University Department of Bioorganic Synthesis, Einsteinweg 55, Leiden, The Netherlands

8. Dmitri V. Filippov

   Leiden University

   Affiliation as printed

   Leiden Institute of Chemistry, Leiden University Department of Bioorganic Synthesis, Einsteinweg 55, Leiden, The Netherlands

9. Bernhard Lüscher Aachen Institute of Biochemistry and Molecular Biology

   RWTH Aachen University

   Affiliation as printed

   Institute of Biochemistry and Molecular Biology, Pauwelsstraße 30, RWTH Aachen University, Aachen, Germany

10. Karla L. H. Feijs corresponding Aachen Institute of Biochemistry and Molecular Biology

    RWTH Aachen University

    Affiliation as printed

    Institute of Biochemistry and Molecular Biology, Pauwelsstraße 30, RWTH Aachen University, Aachen, Germany. kfeijs@ukaachen.de

    Institute of Biochemistry and Molecular Biology, Pauwelsstraße 30, RWTH Aachen University, Aachen, Germany