title: Genetic rationale for microheterogeneity of human diphosphoinositol polyphosphate phosphohydrolase type 2.
abstract: Selective expression of enzymes that adjust the intensity of turnover of diphosphoinositolpolyphosphates may regulate vesicle trafficking and DNA repair. For example, the type 2 human diphosphoinositolpolyphosphate phosphohydrolases (hDIPP2alpha and 2beta) are distinguished by a solitary amino-acid residue; the type 2beta isoform contains Gln86 whereas the type 2alpha isoform does not, yet the latter has 2-5 fold more catalytic activity than its beta counterpart (J. Biol.Chem. (2000) 12730). We discovered that both alpha and beta-type mRNAs were co-expressed in clonal cell-lines. We sought a genetic explanation for this microheterogeneity. Two BACs containing distinct, but intronless, hDIPP2beta genes were cloned. Only one of these genes could potentially give rise to our previously characterized hDIPP2beta mRNA; the other gene has several sequence differences and, in any case, is likely a processed pseudogene. These BACS were mapped to 1q12-q21 and 1p12-p13 by FISH. No analogous intronless hDIPP2alpha gene was detected by analysis of 21 individual genomic DNAs. However, sequence analysis of a third hDIPP2 gene (at 12q21) places the Gln86 CAG codon within an AGCAG pentamer, offering adjacent, alternate intronic 3'-boundaries. Thus, 'intron boundary skidding' by spliceosomes provides a mechanism for yielding both hDIPP2alpha and hDIPP2beta mRNAs. Our studies expand the repertoire of molecular mechanisms regulating diphosphoinositolpolyphosphate metabolism and function.
authors.affiliation: InforMax Inc., 7600 Wisconsin Ave., Bethesda, MD 20814, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Caffrey
authors.forename: S B
authors.initials: SB
authors.lastname: Shears
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D002460:Cell Line; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D002881:Chromosomes, Human, Pair 12; D003106:Colon; D015870:Gene Expression; D018740:Genetic Heterogeneity; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D011544:Pseudogenes; D012333:RNA, Messenger
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; D017766:Acid Anhydride Hydrolases; C116368:diphosphoinositol polyphosphate phosphohydrolase