Cytoplasmic Poly(ADP-Ribose)Polymerase from Mouse Plasmacytoma Free Messenger Ribonucleoprotein Particles: Purification and Characterization

Jesser, M.; Chypre, C.; Hog, F.; Mandel, P.

doi:10.1006/bbrc.1993.2082

Cited by 8 publications

(5 citation statements)

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“…the splicing factor ASF/SF2 (this study, Fig. 4) and several heterogeneous nuclear ribonucleoproteins (46); (ii) both PARP and PAR glycohydrolase activities have been found in cytoplasmic ribonucleoprotein particles (47,48); and (iii) PARP-1 has been shown to possess RNA-binding ability (49). The observation, that ASF/SF2 phosphorylation, but not histone phosphorylation, in HeLa nuclear extracts is sensitive to PAR (Fig.…”

Section: Discussionmentioning

confidence: 57%

Poly(ADP-ribose) Binds to the Splicing Factor ASF/SF2 and Regulates Its Phosphorylation by DNA Topoisomerase I

Malanga

Czubaty

Girstun

et al. 2008

Journal of Biological Chemistry

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Human DNA topoisomerase I plays a dual role in transcription, by controlling DNA supercoiling and by acting as a specific kinase for the SR-protein family of splicing factors. The two activities are mutually exclusive, but the identity of the molecular switch is unknown. Here we identify poly(ADP-ribose) as a physiological regulator of the two topoisomerase I functions. We found that, in the presence of both DNA and the alternative splicing factor/splicing factor 2 (ASF/SF2, a prototypical SRprotein), poly(ADP-ribose) affected topoisomerase I substrate selection and gradually shifted enzyme activity from protein phosphorylation to DNA cleavage. A likely mechanistic explanation was offered by the discovery that poly(ADP-ribose) forms a high affinity complex with ASF/SF2 thereby leaving topoisomerase I available for directing its action onto DNA. We identified two functionally important domains, RRM1 and RS, as specific poly(ADP-ribose) binding targets. Two independent lines of evidence emphasize the potential biological relevance of our findings: (i) in HeLa nuclear extracts, ASF/SF2, but not histone, phosphorylation was inhibited by poly(ADP-ribose); (ii) an in silico study based on gene expression profiling data revealed an increased incidence of alternative splicing within a subset of inflammatory response genes that are dysregulated in cells lacking a functional poly(ADP-ribose) polymerase-1. We propose that poly(ADP-ribose) targeting of topoisomerase I and ASF/SF2 functions may participate in the regulation of gene expression. DNA topoisomerase I (topo I)2 is a constitutively expressed multifunctional enzyme that localizes at active transcription sites (1, 2). Its best known function is to control the topological state of DNA by relieving torsional stress that is generated following DNA strand separation during transcription, replication, and repair (3-5). The catalytic mechanism involves the formation of a DNA⅐topo I complex (cleavage complex) with the enzyme being covalently bound to the 3Ј-end of the cleaved DNA strand through a tyrosine-phosphate ester bond. Cleavage complexes are usually short-lived; their stabilization by compounds of the camptothecin (CPT) family of anticancer drugs may cause DNA strand break accumulation and eventually lead to cell death. Human topo I can relax both negative and positive supercoils by controlled rotation of the DNA strand downstream of the cleavage site followed by break resealing and restoration of an intact DNA duplex.In addition to relaxing supercoiled DNA, human topo I also plays a major role in pre-mRNA splicing, being endowed with a protein kinase activity targeted at a group of splicing factors of the serine-arginine (SR)-rich protein family (6). SR-proteins function both as components of the basal RNA splicing machinery and as regulators of alternative splicing (7, 8). Moreover, SR-proteins are involved in the control of mRNA transport and stability (8, 9) and contribute to the maintenance of genomic stability (10). SR-proteins are structurally characterized ...

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Section: Discussionmentioning

confidence: 57%

Poly(ADP-ribose) Binds to the Splicing Factor ASF/SF2 and Regulates Its Phosphorylation by DNA Topoisomerase I

Malanga

Czubaty

Girstun

et al. 2008

Journal of Biological Chemistry

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“…Work from our laboratory also shows that p53 is a target for poly(ADP-ribose) binding and that the p53 function is also affected by these polymers (64). Second, cytoplasmic forms of PARP have been reported in a number of cell extracts including free ribosomes and polysomes of Hela cells (65), spermatocytes (66,67), and free messenger ribonucleoprotein particles in mouse plasmacytoma (65). Third, for poly(ADP-ribose) to appear in the cytosol, the Although there is no direct in vivo evidence for a role of polyADP-ribosylation in the biology of MARCKS proteins, one report suggests that such an interaction might take place: Methyl methanesulfonate (MMS), a tumorgenic DNA alkylating agent (71,72), inhibits the PKC-dependent phosphorylation of MARCKS in cultured NIH 3T3 cells (73).…”

Section: Discussionmentioning

confidence: 83%

Poly(ADP-ribose) Modulates the Properties of MARCKS Proteins

et al. 1998

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In mammalian cells, the formation of DNA strand breaks is accompanied by synthesis of poly(ADP-ribose). This nucleic acid-like homopolymer may modulate protein functions by covalent and/or noncovalent interactions. Here we show that poly(ADP-ribose) binds strongly to the proteins of the myristoylated alanine-rich C kinase substrate (MARCKS) family, MARCKS and MARCKS-related protein (also MacMARCKS or F52). MARCKS proteins are myristoylated proteins associated with membranes and the actin cytoskeleton. As targets for both protein kinase C (PKC) and calmodulin (CaM), MARCKS proteins are thought to mediate cross-talk between these two signal transduction pathways. Dot blot assays show that poly(ADP-ribose) binds to MARCKS proteins at the highly basic effector domain. Complex formation between MARCKS-related protein and CaM as well as phosphorylation of MARCKS-related protein by the catalytic subunit of PKC are strongly inhibited by equimolar amounts of poly(ADP-ribose), suggesting a high affinity of poly(ADP-ribose) for MARCKS-related protein. Binding of MARCKS-related protein to membranes is also inhibited by poly(ADP-ribose). Finally, poly(ADP-ribose) efficiently reverses the actin-filament bundling activity of a peptide corresponding to the effector domain and inhibits the formation of actin filaments in vitro. Our results suggest that MARCKS proteins and actin could be targets of the poly(ADP-ribose) DNA damage signal pathway.

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“…These cytoplasmic PARP activities were identified in multiple mammalian cell types (HeLa, macrophages, erythroblasts, plasma cells and neurons) and tissues (brain and liver extracts) suggesting that the modification is ubiquitous. 24,25 Further functions for cytoplasmic pADPr were suggested by the activities of its degradative enzyme, pADPr glycohydrolase (PARG). in vitro, where the initial and elongation steps were separated.…”

Section: Parp Functions Beyond the Nucleusmentioning

confidence: 99%

“…Such fractions were enriched in factors that regulate translation potential and decay of mRNAs. 24,[26][27][28] Such correlation led to the hypothesis that pADPr may be involved in post-transcriptional mRNA regulation. This hypothesis was further supported by the recent discovery of two PARPs, PARP-12 and -13, that localize to the cytoplasm and contain CCCH type zinc finger RNA-binding domains.…”

Section: Multiple Cytoplasmic Parpsmentioning

confidence: 99%

Poly(ADP-ribose) regulates post-transcriptional gene regulation in the cytoplasm

et al. 2012

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Since its discovery in 1963, poly(ADP-ribose) (pADPr) has been shown to play important functions in the nucleus of multicellular eukaryotes. Each of these functions centers upon DNA metabolism, including DNA-damage repair, chromatin remodeling, transcription and telomere functions. We recently described two novel functions for pADPr in the cytoplasm, both of which involve RNA metabolism - 1) the assembly of cytoplasmic stress granules, cellular macrostructures that aggregate translationally stalled mRNA/protein complexes, and 2) modulation of microRNA activities. Multiple stress granule-localized, post-transcriptional gene regulators, including microRNA-binding argonaute family members, are substrates for pADPr modification and are increasingly modified by pADPr upon stress. Interestingly, the cytoplasmic RNA regulatory functions for PARPs are likely mediated through activities of catalytically inactive PARP-13/ARTD13/ZC3HAV1/ZAP and mono/poly(ADP-ribose)-synthesizing enzymes, including PARP-5a/ARTD5/TNKS1, PARP-12/ARTD12/ZC3HDC1 and PARP-15/ARTD7/BAL3. These data are consistent with other recent work, which suggests that mono(ADP-ribosyl)ated residues can be poly(ADP-ribosyl)ated by different enzymes.

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Cytoplasmic Poly(ADP-Ribose)Polymerase from Mouse Plasmacytoma Free Messenger Ribonucleoprotein Particles: Purification and Characterization

Cited by 8 publications

References 0 publications

Poly(ADP-ribose) Binds to the Splicing Factor ASF/SF2 and Regulates Its Phosphorylation by DNA Topoisomerase I

Poly(ADP-ribose) Binds to the Splicing Factor ASF/SF2 and Regulates Its Phosphorylation by DNA Topoisomerase I

Poly(ADP-ribose) Modulates the Properties of MARCKS Proteins

Poly(ADP-ribose) regulates post-transcriptional gene regulation in the cytoplasm

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