Structures and Mechanisms of Enzymes Employed in the Synthesis and Degradation of PARP-Dependent Protein ADP-Ribosylation

Barkauskaite, Eva; Jankevicius, Gytis; Ahel, Ivan

doi:10.1016/j.molcel.2015.05.007

Cited by 224 publications

(248 citation statements)

References 104 publications

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“…[1][2][3] PARP-1 has been a promising target for cancer therapy; however, clinical trials utilizing PARP inhibitors for monotherapy have shown mixed response rates. 4 These pitfalls have directed PARP inhibitors to the adjuvant setting where combinatorial approaches offer greater therapeutic efficacy with limited toxicity.…”

Section: Introductionmentioning

confidence: 99%

PARP-1 Expression Quantified by [¹⁸F]FluorThanatrace: A Biomarker of Response to PARP Inhibition Adjuvant to Radiation Therapy

Effron

Makvandi

Lin

et al. 2017

Cancer Biotherapy and Radiopharmaceuticals

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Introduction: Poly (ADP-ribose) polymerase 1 (PARP-1) is the major target of clinical PARP inhibitors and is a potential predictive biomarker for response to therapy. Due to the limited success of PARP inhibitors as monotherapy, investigators have shifted the clinical role of PARP inhibitors to the adjuvant setting. In this study, we evaluate the radiotracer [18 F]FluorThanatrace ([ 18 F]FTT) as a marker of PARP expression in vitro and the associated biological implications of PARP-1 expression in PARP inhibitor treatment adjuvant to radiation therapy. Materials and Methods: SNU-251 (BRCA1-mutant) and SKOV3 (BRCA1-WT) cell lines were evaluated in vitro by using the radiotracer [18 F]FTT. Pharmacological binding assays were performed at baseline and were correlated with PARP-1 protein expression measured by Western blot protein analysis. Cell viability and clonogenic assays were used to characterize in vitro cytotoxicity for treatments, including: PARP inhibitors alone, radiation alone, and PARP inhibitor adjuvant to radiation. Western blot protein analysis was used to assess response to treatment by using cH2AX to measure DNA damage and PAR to measure the catalytic inhibition of PARP. Results: [

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Section: Introductionmentioning

confidence: 99%

PARP-1 Expression Quantified by [¹⁸F]FluorThanatrace: A Biomarker of Response to PARP Inhibition Adjuvant to Radiation Therapy

Effron

Makvandi

Lin

et al. 2017

Cancer Biotherapy and Radiopharmaceuticals

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“…ADP-ribosylation also functions as a signaling scaffold for the recruitment of binding proteins to ADPr-modified targets 17–22 . Importantly, ADPr modifications are reversible 23–26 , and the duration of the signaling that results from ADP-ribosylation of targets is dependent on the kinetics of turnover at the modification site 27–29 . Therefore, it is critical to understand how and where targets are modified by ARTs.…”

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confidence: 99%

Insights into the biogenesis, function, and regulation of ADP-ribosylation

2018

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ADP-ribosylation—the transfer of ADP-ribose (ADPr) from NAD+ onto target molecules—is catalyzed by members of the ADP-ribosyltransferase (ART) superfamily of proteins, found in all kingdoms of life. Modification of amino acids in protein targets by ADPr regulates critical cellular pathways in eukaryotes and underlies the pathogenicity of certain bacteria. Several members of the ART superfamily are highly relevant for disease; these include the poly(ADP-ribose) polymerases (PARPs), recently shown to be important cancer targets, and the bacterial toxins diphtheria toxin and cholera toxin, long known to be responsible for the symptoms of diphtheria and cholera that result in morbidity. In this Review, we discuss the functions of amino acid ADPr modifications and the ART proteins that make them, the nature of the chemical linkage between ADPr and its targets and how this impacts function and stability, and the way that ARTs select specific amino acids in targets to modify.

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“…That is why PARylation is subjected to tight control by the enzymes that break down PAR and remove ADP-ribose residues from modified proteins [161]. The key ADP-ribose-degrading enzyme is poly(ADP-ribose)glycohydrolase (PARG), which exhibits endo- and exo-hydrolase activities; the latter activity being dominant over the first one [162].…”

Section: Poly(adp-ribose) and Poly(adp-ribosyl)ationmentioning

confidence: 99%

At the Interface of Three Nucleic Acids: The Role of RNA-Binding Proteins and Poly(ADP-ribose) in DNA Repair

Alemasova

Lavrik

2017

Acta Naturae

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RNA-binding proteins (RBPs) regulate RNA metabolism, from synthesis to decay. When bound to RNA, RBPs act as guardians of the genome integrity at different levels, from DNA damage prevention to the post-transcriptional regulation of gene expression. Recently, RBPs have been shown to participate in DNA repair. This fact is of special interest as DNA repair pathways do not generally involve RNA. DNA damage in higher organisms triggers the formation of the RNA-like polymer – poly(ADP-ribose) (PAR). Nucleic acid-like properties allow PAR to recruit DNA- and RNA-binding proteins to the site of DNA damage. It is suggested that poly(ADP-ribose) and RBPs not only modulate the activities of DNA repair factors, but that they also play an important role in the formation of transient repairosome complexes in the nucleus. Cytoplasmic biomolecules are subjected to similar sorting during the formation of RNA assemblages by functionally related mRNAs and promiscuous RBPs. The Y-box-binding protein 1 (YB-1) is the major component of cytoplasmic RNA granules. Although YB-1 is a classic RNA-binding protein, it is now regarded as a non-canonical factor of DNA repair.

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Structures and Mechanisms of Enzymes Employed in the Synthesis and Degradation of PARP-Dependent Protein ADP-Ribosylation

Cited by 224 publications

References 104 publications

PARP-1 Expression Quantified by [¹⁸F]FluorThanatrace: A Biomarker of Response to PARP Inhibition Adjuvant to Radiation Therapy

PARP-1 Expression Quantified by [¹⁸F]FluorThanatrace: A Biomarker of Response to PARP Inhibition Adjuvant to Radiation Therapy

Insights into the biogenesis, function, and regulation of ADP-ribosylation

At the Interface of Three Nucleic Acids: The Role of RNA-Binding Proteins and Poly(ADP-ribose) in DNA Repair

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Structures and Mechanisms of Enzymes Employed in the Synthesis and Degradation of PARP-Dependent Protein ADP-Ribosylation

Cited by 224 publications

References 104 publications

PARP-1 Expression Quantified by [18F]FluorThanatrace: A Biomarker of Response to PARP Inhibition Adjuvant to Radiation Therapy

PARP-1 Expression Quantified by [18F]FluorThanatrace: A Biomarker of Response to PARP Inhibition Adjuvant to Radiation Therapy

Insights into the biogenesis, function, and regulation of ADP-ribosylation

At the Interface of Three Nucleic Acids: The Role of RNA-Binding Proteins and Poly(ADP-ribose) in DNA Repair

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Product

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PARP-1 Expression Quantified by [¹⁸F]FluorThanatrace: A Biomarker of Response to PARP Inhibition Adjuvant to Radiation Therapy

PARP-1 Expression Quantified by [¹⁸F]FluorThanatrace: A Biomarker of Response to PARP Inhibition Adjuvant to Radiation Therapy