title: Human poly(ADP-ribose) glycohydrolase is expressed in alternative splice variants yielding isoforms that localize to different cell compartments.
abstract: Poly(ADP-ribose) glycohydrolase (PARG) is the only protein known to catalyze hydrolysis of ADP-ribose (ADPR) polymers to free ADP-ribose. While numerous genes encode different poly(ADP-ribose) polymerases (PARPs) that all synthesize ADP-ribose polymer, only a single gene coding for PARG has been detected in mammalian cells. Here, we describe two splice variants of human PARG mRNA, which lead to expression of PARG isoforms of 102 kDa (hPARG102) and 99 kDa (hPARG99) in addition to the full-length PARG protein (hPARG111). These splice variants differ from hPARG111 by the lack of exon 1 (hPARG102) or exons 1 and 2 (hPARG99). They are generated by the utilization of ambiguous splice donor sites in the PARG gene 5' untranslated region. The hPARG111 isoform localizes to the nucleus, whereas hPARG102 and hPARG99 are cytoplasmic proteins. The nuclear targeting of hPARG111 is due to a nuclear localization signal (NLS) in exon 1 that was mapped to the amino acids (aa) (10)CTKRPRW(16). Immunocytochemistry, immunoblotting, and PARG enzyme activity measurements show that the cytoplasmic isoforms of PARG account for most of the PARG activity in cells in the absence and presence of genotoxic stress. The predominantly cytoplasmic location of cellular PARG is intriguing as most known cellular PARPs have a nuclear localization.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Mirella L
authors.initials: ML
authors.lastname: Meyer-Ficca
authors.forename: Ralph G
authors.initials: RG
authors.lastname: Meyer
authors.forename: Donna L
authors.initials: DL
authors.lastname: Coyle
authors.forename: Elaine L
authors.initials: EL
authors.lastname: Jacobson
authors.forename: Myron K
authors.initials: MK
authors.lastname: Jacobson
mesh_terms: D020121:5' Untranslated Regions; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D017398:Alternative Splicing; D015153:Blotting, Western; D002451:Cell Compartmentation; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry; D005091:Exons; D014644:Genetic Variation; D006026:Glycoside Hydrolases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D019913:Nuclear Localization Signals; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020539:Sequence Analysis, Protein
chemical_list: D020121:5' Untranslated Regions; D007527:Isoenzymes; D019913:Nuclear Localization Signals; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D000246:Adenosine Diphosphate Ribose; D008156:Luciferases; D006026:Glycoside Hydrolases