title: ADP-ribosylhydrolase 3 (ARH3), not poly(ADP-ribose) glycohydrolase (PARG) isoforms, is responsible for degradation of mitochondrial matrix-associated poly(ADP-ribose).
abstract: Important cellular processes are regulated by poly(ADP-ribosyl)ation. This protein modification is catalyzed mainly by nuclear poly(ADP-ribose) polymerase (PARP) 1 in response to DNA damage. Cytosolic PARP isoforms have been described, whereas the presence of poly(ADP-ribose) (PAR) metabolism in mitochondria is controversial. PAR is degraded by poly(ADP-ribose) glycohydrolase (PARG). Recently, ADP-ribosylhydrolase 3 (ARH3) was also shown to catalyze PAR-degradation in vitro. PARG is encoded by a single, essential gene. One nuclear and three cytosolic isoforms result from alternative splicing. The presence and origin of a mitochondrial PARG is still unresolved. We establish here the genetic background of a human mitochondrial PARG isoform and investigate the molecular basis for mitochondrial poly(ADP-ribose) degradation. In common with a cytosolic 60-kDa human PARG isoform, the mitochondrial protein did not catalyze PAR degradation because of the absence of exon 5-encoded residues. In mice, we identified a transcript encoding an inactive cytosolic 52-kDa PARG lacking the mitochondrial targeting sequence and a substantial portion of exon 5. Thus, mammalian PARG genes encode isoforms that do not catalyze PAR degradation. On the other hand, embryonic fibroblasts from ARH3(-/-) mice lack most of the mitochondrial PAR degrading activity detected in wild-type cells, demonstrating a potential involvement of ARH3 in PAR metabolism.
authors.affiliation: Department of Molecular Biology, University of Bergen, Postbox 7803, 5020 Bergen, Norway.
authors.forename: Marc
authors.initials: M
authors.lastname: Niere
authors.forename: Masato
authors.initials: M
authors.lastname: Mashimo
authors.forename: Line
authors.initials: L
authors.lastname: Agledal
authors.forename: Christian
authors.initials: C
authors.lastname: Dölle
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasamatsu
authors.forename: Jiro
authors.initials: J
authors.lastname: Kato
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
authors.forename: Mathias
authors.initials: M
authors.lastname: Ziegler
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005091:Exons / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006026:Glycoside Hydrolases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D011064:Poly Adenosine Diphosphate Ribose / Q000235:genetics / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; D007527:Isoenzymes; D011064:Poly Adenosine Diphosphate Ribose; D006026:Glycoside Hydrolases; C508145:ADPRS protein, human