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Query: UNIPROT:P06889 (Mol)
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At least one of the procyclic acidic repetitive protein (PARP or procyclin) loci of Trypanosoma brucei is a small (5- to 6-kilobase) polycistronic transcription unit which is transcribed in an alpha-amanitin-resistant manner. Its single promoter, as mapped by run-on transcription analysis and UV inactivation of transcription, is located immediately upstream of the first alpha-PARP gene. Transcription termination occurs in a region approximately 3 kilobases downstream of the beta-PARP gene. The location of the promoter was confirmed by its ability to direct transcription of the bacterial chloramphenicol acetyltransferase gene in insect-form (procyclic) T. brucei. The putative PARP promoter is located in the region between the 3' splice acceptor site (nucleotide position 0) and nucleotide position -196 upstream of the alpha-PARP genes. Regulatory regions influencing the levels of PARP expression may be located further upstream. We conclude that a single promoter, which is located very close to the 3' splice acceptor site of the alpha-PARP genes, directs the transcription of a small, polycistronic, and alpha-amanitin-resistant transcription unit.
Mol Cell Biol 1990 Jul
PMID:Procyclic acidic repetitive protein (PARP) genes located in an unusually small alpha-amanitin-resistant transcription unit: PARP promoter activity assayed by transient DNA transfection of Trypanosoma brucei. 169 12

The genes for the variant surface glycoprotein (VSG) and procyclin are expressed in a mutually exclusive manner during the life cycle of Trypanosoma brucei and synthesize the most abundant mRNAs specific to the bloodstream and procyclic stages of the parasite, respectively. Genes belonging to the polycistronic transcription unit of the VSG gene (expression site-associated genes [ESAGs]) are uniquely expressed in the bloodstream form, but some members of ESAG families (genes related to ESAGs [GRESAGs]) are independently transcribed outside the VSG gene expression site. We report here that a gene related to ESAG 2, GRESAG 2.1, is present and expressed in a procyclin gene transcription unit (PARP A locus), which is polycistronic. Members of the ESAG 2 family are thus present in the two major differentially stage-regulated transcription units of this parasite.
Mol Cell Biol 1991 Mar
PMID:A similar gene is shared by both the variant surface glycoprotein and procyclin gene transcription units of Trypanosoma brucei. 199 4

Poly(ADP-ribosyl)ation is a posttranslational modification of nuclear proteins catalyzed by poly(ADP-ribose) polymerase (PARP; EC 2.4.2.30), with NAD+ serving as the substrate. PARP is strongly activated upon recognition of DNA strand breaks by its DNA-binding domain. Experiments with low-molecular-weight inhibitors of PARP have led to the view that PARP activity plays a role in DNA repair and possibly also in DNA replication, cell proliferation, and differentiation. Accumulating evidence for nonspecific inhibitor effects prompted us to develop a molecular genetic system to inhibit PARP in living cells, i.e., to overexpress selectively the DNA-binding domain of PARP as a dominant negative mutant. Here we report on a cell culture system which allows inducible, high-level expression of the DNA-binding domain. Induction of this domain leads to about 90% reduction of poly(ADP-ribose) accumulation after gamma-irradiation and sensitizes cells to the cytotoxic effect of gamma-irradiation and of N-methyl-N'-nitro-N-nitrosoguanidine. In contrast, induction does not affect normal cellular proliferation or the replication of a transfected polyomavirus replicon. Thus, trans-dominant inhibition of the poly(ADP-ribose) accumulation occurring after gamma-irradiation or N-methyl-N'-nitro-N-nitrosoguanidine is specifically associated with a disturbance of the cellular recovery from the inflicted damage.
Mol Cell Biol 1995 Jun
PMID:trans-dominant inhibition of poly(ADP-ribosyl)ation sensitizes cells against gamma-irradiation and N-methyl-N'-nitro-N-nitrosoguanidine but does not limit DNA replication of a polyomavirus replicon. 776 Aug 11

Poly(ADP-ribose) polymerase (PARP) participates in the intricate network of systems developed by the eukaryotic cell to cope with the numerous environmental and endogenous genetoxic agents. Cloning of the PARP gene has allowed the development of genetic and molecular approaches to elucidate the structure and the function of this abundant and highly conserved enzyme. This article summarizes our present knowledge in this field.
Mol Cell Biochem 1994 Sep
PMID:Structure and function of poly(ADP-ribose) polymerase. 789 58

Recently, two deoxyribose analogs of beta NAD+ (2'-deoxy and 3'-deoxyNAD+) have been synthesized and purified in this laboratory. Whereas 2'-deoxyNAD+ was an efficient substrate for arg-specific mon(ADP-ribosyl) transferases, it was not a substrate for poly(ADP-ribose) polymerase (PARP). Instead, it was a non-competitive inhibitor of beta NAD+ in the ADP-ribose polymerization reaction catalyzed by PARP. Thus, 2'-deoxyNAD+ has been utilized to distinguish between mono(ADP-ribose) and poly(ADP-ribose) acceptor proteins. 2'-deoxyNAD+ has also been used to characterize the arg-specific mono(2'-deoxyADP-ribosyl)ation reaction of PARP with cholera toxin or avian mono(ADP-ribosyl)transferase. By contrast, 3'-deoxyNAD+ can effectively be utilized as a substrate by PARP. However, while the estimated Km and Kcat of polymerization with 3'-deoxyNAD+ were 20 microM and 0.11 moles/sec, the Km and Kcat with beta NAD+ as a substrate were 59 microM and 1.29 moles/sec, respectively. Determination of the average size of 3'-deoxyADP-ribose polymers indicated that chains no larger than four residues are synthesized with this substrate. Thus, the utilization of 3'-deoxyNAD+ has facilitated the electrophoretic identification of poly(ADP-ribose) acceptor proteins in mammalian chromatin.
Mol Cell Biochem 1994 Sep
PMID:DeoxyNAD and deoxyADP-ribosylation of proteins. 789 66

In this minireview, we summarize recent advances on the enzymology of ADP-ribose polymer synthesis. First, a short discussion of the primary structure and cloning of poly(ADP-ribose) polymerase (PARP) [EC 2.4.2.30], the enzyme that catalyzes the synthesis of poly(ADP-ribose), is presented. A catalytic distinction between the multiple enzymatic activities of PARP is established. The direction of ADP-ribose chain growth as well as the molecular mechanism of the automodification reaction catalyzed by PARP are described. Current approaches to dissect ADP-ribose polymer synthesis into individual reactions of initiation, elongation and branching, as well as a partial mechanistic characterization of the ADP-ribose elongation reaction at the chemical level are also presented. Finally, recent developments in the catalytic characterization of PARP by site-directed mutagenesis are also briefly summarized.
Mol Cell Biochem 1994 Sep
PMID:Enzymology of ADP-ribose polymer synthesis. 789 72

Homogeneously purified poly(ADP-ribose) polymerase (PARP) specifically stimulated the activity of immunoaffinity-purified calf or human DNA polymerase alpha by about 6 to 60-fold. Apparently, poly(ADP-ribosyl)ation of DNA polymerase alpha was not necessary for the stimulation. The effects of PARP on DNA polymerase alpha were biphasic: at very low concentrations of DNA, it rather inhibited its activity, whereas, at higher DNA concentrations, PARP greatly stimulated it. The autopoly(ADP-ribosyl)ation of PARP suppressed both its stimulatory and inhibitory effects. By immunoprecipitation with an anti-DNA polymerase alpha antibody, it was clearly shown that PARP may be physically associated with DNA polymerase alpha. Stimulation of DNA polymerase alpha may be attributed to the physical association between the two, rather than to the DNA-binding capacity of PARP, since the PARP fragment containing only the DNA binding domain showed little stimulatory activity. The existence of PARP-DNA polymerase alpha complexes were also detected in crude extracts of calf thymus.
Mol Cell Biochem 1994 Sep
PMID:Interaction of poly(ADP-ribose)polymerase with DNA polymerase alpha. 789 73

Poly(ADP-ribosyl)ation is a eukaryotic posttranslational protein modification catalyzed by poly(ADP-ribose) polymerase (PARP), a highly conserved nuclear enzyme which uses NAD as substrate. We have previously tested PARP activity in permeabilized mononuclear blood cells (MNC) from 13 mammalian species as a function of the species-specific life span. A direct and maximal stimulus of PARP activation was provided by including saturating amounts of a double-stranded oligonucleotide in the PARP-reaction buffer. The data yielded a strong positive correlation between PARP activities and the species' maximal life spans (r = 0.84; p << 0.001). Here, we investigated the formation of poly(ADP-ribose) in living MNC from two mammalian species with widely differing longevity (rat and man) by immunofluorescence detection of poly(ADP-ribose). The fraction of positive cells was recorded, following gamma-irradiation of intact MNC, as a semiquantitative estimation of poly(ADP-ribose) formation. Human samples displayed a significantly higher percentage of positivity than did those from rats, consistent with our previous results on permeabilized cells. While rat MNC had a higher NAD content than human MNC, the number of radiation-induced DNA strand breaks was not significantly different in the two species. Since poly(ADP-ribosyl)ation is apparently involved in DNA repair and the cellular recovery from DNA damage, we speculate that the higher poly(ADP-ribosyl)ation capacity of long-lived species might more efficiently help to slow down the accumulation of unrepaired DNA damage and of genetic alterations, as compared with short-lived species.
Mol Cell Biochem 1994 Sep
PMID:Poly(ADP-ribose) polymerase activity in intact or permeabilized leukocytes from mammalian species of different longevity. 789 80

Nearly all trypanosome mRNAs are synthesized as polycistronic precursors, from which mature mRNAs are excised by trans splicing and polyadenylation. Polyadenylation of a procyclic acidic repetitive protein (PARP, or procyclin) transcript was studied by transient transfection of constructs bearing a chloramphenicol acetyltransferase gene linked to the PARP intergenic region. Polyadenylation usually occurred at A residues, about 100 bases upstream of a trans-splicing acceptor signal. The wild-type polyadenylation site has a cryptic trans-splicing signal about 100 bp downstream: deletion or inversion of this signal results in polyadenylation at multiple sites, upstream of other cryptic trans-splicing signals. The PARP mRNA precursor appears to contain a hierarchy of possible processing signals, the function of cryptic ones being revealed only when the dominant ones are deleted or moved. Correct polyadenylation can be restored by addition of trans-splicing signals from other loci. The results indicate that polyadenylation is coupled to downstream trans splicing but that the products of the trans-splicing reaction are not necessarily functional mRNAs.
Mol Cell Biol 1994 Nov
PMID:Hierarchies of RNA-processing signals in a trypanosome surface antigen mRNA precursor. 793 57

The procyclic acidic repetitive protein (procyclin) and variant surface glycoprotein genes of Trypanosoma brucei are transcribed by a polymerase sharing many features with RNA polymerase I. Mutational analyses on the PARP and ribosomal RNA promoters have shown that sequences important for promoter activity are concentrated 20-60 bp upstream of the transcription initiation site. The results of gel mobility shift assays using synthetic oligonucleotides spanning of these regions indicated the presence in trypanosomal extracts of factors capable of binding each promoter in a highly specific fashion. There was no evidence that the PARP, VSG and rRNA promoter fragments bound the same factor.
Mol Biochem Parasitol 1994 May
PMID:Factors that bind to RNA polymerase I promoter sequences of Trypanosoma brucei. 793 33


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