A cellular defense pathway regulating transcription through poly(ADP-ribosyl)ation in response to DNA damage

Vispé, Stéphane; Yung, Tetsu M.C.; Ritchot, Janelle; Serizawa, Hiroaki; Satoh, Masahiko S.

doi:10.1073/pnas.170280397

Cited by 71 publications

(59 citation statements)

References 43 publications

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“…PARP-deficient mouse fibroblasts exhibit elevated levels of SCEs (de Murcia et al, 1997;Wang et al, 1997), suggesting that BRCA1 and PARP-1 regulate the fidelity of SCE. Also, PARP-1 functions as a transcriptional coactivator (Meisterernst et al, 1997), inhibits transcription during DNA damage (Taniguchi et al, 1982), and enhances transcript elongation (Vispe et al, 2000), consistent with the observed transcriptioncoupled repair defect in BRCA1-deficient mouse embryonic stem cells (Abbott et al, 1999;Gowen et al, 1998) and with the transcription function of BRCA1 (Haile and Parvin, 1999;Schlegel et al, 2000). However, acute loss of PARP-1 expression is not sufficient to account for all roles attributed to BRCA1.…”

Section: Discussionmentioning

confidence: 79%

Overexpression of a protein fragment of RNA helicase A causes inhibition of endogenous BRCA1 function and defects in ploidy and cytokinesis in mammary epithelial cells

2003

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The breast-and ovarian-specific tumor suppressor, BRCA1, has been implicated to function in many nuclear processes, including DNA damage repair, recombination, transcription, ubiquitination, cell cycle checkpoint enforcement, and centrosome regulation. Utilizing a previously described interaction between BRCA1 and RNA helicase A (RHA), we have developed a dominant-negative approach to block BRCA1 function in human breast epithelial cells. Overexpression of a truncated RHA peptide that can bind to the BRCA1 carboxy-terminus prevents normal BRCA1 function, such as BRCA1 association with nuclear foci following DNA damage. Overexpression of this dominant-negative protein induces pleomorphic nuclei, aberrant mitoses with extra centrosomes, and tetraploidy. This model system allows us to observe changes to mammary epithelial cells that occur acutely following loss of BRCA1 function. Furthermore, inhibition of BRCA1 via overexpressing the RHA fragment coincides with a reduction in PARP-1 protein expression, suggesting a possible mechanism for BRCA1 in the maintenance of genomic integrity. Oncogene (2003) 22, 983-991.

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Section: Discussionmentioning

confidence: 79%

Overexpression of a protein fragment of RNA helicase A causes inhibition of endogenous BRCA1 function and defects in ploidy and cytokinesis in mammary epithelial cells

2003

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“…Vispé et al (2000) provide evidence for such a previously unrecognized pathway: PARP-1 is found to reduce the rate of transcription elongation by pol II, suggesting regulation at the level of PARP-RNA complexes. In damaged cells, binding of PARP to DNA breaks activates the enzyme in the presence of NAD + , which promotes extensive automodification and results in its dissociation from DNA.…”

Section: Autoregulatory Circuitsmentioning

confidence: 81%

Scaffold/Matrix Attachment Regions (S/MARs): Relevance for Disease and Therapy

Gluch

Vidaković²,

Bode

2008

Handbook of Experimental Pharmacology

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“…Although the evidence supporting such a mechanism is not yet available, it is conceivable that the sharing of components such as PARP by DNA repair and transcription allows both events to control cellular survival in response to ionizing radiation and DNA-damaging treatments. In support of this mechanism, PARP-dependent inhibition of transcription elongation by RNA polymerase II in undamaged cells and up-regulation of mRNA synthesis in response to DNA damage have been recently demonstrated both in vitro and in vivo (13). Studies testing this hypothesis are underway.…”

Section: Parp Protein Binds To the 5ј-flankingmentioning

confidence: 90%

Transcriptional Repression by Binding of Poly(ADP-ribose) Polymerase to Promoter Sequences

Soldatenkov¹,

Chasovskikh²,

Potaman³

et al. 2002

Journal of Biological Chemistry

104

106

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Poly(ADP-ribose) polymerase (PARP) is a DNA-binding enzyme that plays roles in response to DNA damage, apoptosis, and genetic stability. Recent evidence has implicated PARP in transcription of eukaryotic genes. However, the existing paradigm tying PARP function to the presence of DNA strand breaks does not provide a mechanism by which it may be recruited to gene-regulating domains in the absence of DNA damage. Here we report that PARP can bind to the DNA secondary structures (hairpins) in heteroduplex DNA in a DNA end-independent fashion and that automodification of PARP in the presence of NAD ؉ inhibited its hairpin binding activity. Atomic force microscopic images show that in vitro PARP protein has a preference for the promoter region of the PARP gene in superhelical DNA where the dyad symmetry elements likely form hairpins according to DNase probing. Using a chromatin cross-linking and immunoprecipitation assay we show that PARP protein binds to the chromosomal PARP promoter in vivo. Reporter gene assays have revealed that the transcriptional activity of the PARP promoter is 4 -5-fold greater in PARP knockout cells than in wild type fibroblasts. Reintroduction of vectors expressing full-length PARP protein or its truncated mutant (DNA-binding domain retained but lacking catalytic activity) into PARP ؊/؊ cells has conferred transcriptional down-regulation of the PARP gene promoter. These data provide support for PARP protein as a potent regulator of transcription including down-regulation of its own promoter.Poly(ADP-ribose) polymerase (PARP, 1 EC 2.4.2.30) is a chromatin-associated enzyme that catalyzes the transfer of successive units of the ADP-ribose moiety from NAD ϩ to itself and other nuclear acceptor proteins (1). PARP is a zinc fingercontaining protein, which allows enzyme binding to either double or single strand DNA breaks without any apparent sequence preference (2, 3). The catalytic activity of PARP is strictly dependent on the presence of strand breaks in DNA and is modulated by the level of automodification (4,5). Data from many studies show that PARP is involved in numerous biological functions, all of which are associated with breaking and rejoining DNA strands, and it plays a pivotal role in DNA damage repair (2, 6 -8).Recent studies have implicated PARP in transcription of eukaryotic genes (9 -16). PARP-dependent gene regulation involves poly(ADP-ribosyl)ation of transcription factors, which, in turn, prevents their binding to specific promoter sequences (10). The basal transcription factors TFIIF and TEF-1 as well as transcription factors TATA box-binding protein, YY1, SP-1, cAMP-response element-binding protein, p53, and NFB are all highly specific substrates for poly(ADP-ribosyl)ation (10,11,14,16). PARP may also interact directly with gene promoters. For instance, recombinant full-length PARP bound the DNA sequences within the MCAT1 regulatory element (11) and to the DF4 protein binding site of the Pax-6 gene neuroretinaspecific enhancer (17). Furthermore, PARP involvement in the active...

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A cellular defense pathway regulating transcription through poly(ADP-ribosyl)ation in response to DNA damage

Cited by 71 publications

References 43 publications

Overexpression of a protein fragment of RNA helicase A causes inhibition of endogenous BRCA1 function and defects in ploidy and cytokinesis in mammary epithelial cells

Overexpression of a protein fragment of RNA helicase A causes inhibition of endogenous BRCA1 function and defects in ploidy and cytokinesis in mammary epithelial cells

Scaffold/Matrix Attachment Regions (S/MARs): Relevance for Disease and Therapy

Transcriptional Repression by Binding of Poly(ADP-ribose) Polymerase to Promoter Sequences

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