Poly(ADP-Ribose) Glycohydrolase (PARG) vs. Poly(ADP-Ribose) Polymerase (PARP) – Function in Genome Maintenance and Relevance of Inhibitors for Anti-cancer Therapy

Harrision, Daniel; Gravells, Polly; Thompson, Ruth; Bryant, Helen E.

doi:10.3389/fmolb.2020.00191

Cited by 67 publications

(51 citation statements)

References 235 publications

(327 reference statements)

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“…The high complexity of ADP-ribosyl associated pathways makes the involved proteins notoriously hard to study (Bonfiglio et al, 2020;Lüscher et al, 2018). While potent and specific inhibitors against many of the ADP-ribosyl transferases fundamentally helped to broaden our understanding of these enzymes (Durkacz et al, 1980;Huang et al, 2009;Kirby et al, 2018;Venkannagari et al, 2016;Wang et al, 2018), such inhibitors against ADP-ribosyl readers and erasers are still scarcely available or in early stages of development (Harrision et al, 2020;James et al, 2016;Liu et al, 2020;Palazzo and Ahel, 2018;Schuller et al, 2017). It was suggested that a possible bottleneck for the discovery of inhibitors is due to the lack of accessible high-throughput technologies (Schuller et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

A molecular toolbox for ADP-ribosyl binding proteins

Sowa

Galera‐Prat

Wazir

et al. 2021

Preprint

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Proteins interacting with ADP-ribosyl groups are often involved in disease-related pathways or in viral infections, which makes them attractive targets for the development of inhibitors. Our goal was to develop a robust and accessible assay technology that is suitable for high-throughput screening and applicable to a wide range of proteins acting as either hydrolysing or non-hydrolysing binders of mono- and poly-ADP-ribosyl groups. As a foundation of our work, we developed a C-terminal protein fusion tag based on a Gi protein alpha subunit peptide (GAP), which allows for site-specific introduction of cysteine-linked mono- and poly-ADP-ribosyl groups as well as chemical ADP-ribosyl analogs. By fusion of the GAP-tag and ADP-ribosyl binders to fluorescent proteins, we were able to generate robust FRET signals and the interaction with 22 previously described ADP-ribosyl-binders was confirmed. To demonstrate the applicability of this binding assay for high-throughput screening, we utilized it to screen for inhibitors of the SARS-CoV-2 nsp3 macrodomain and identified the drug suramin as a moderate yet unspecific inhibitor of this protein. To complement the binding technology, we prepared high-affinity ADP-ribosyl binders fused to a nanoluciferase, which enabled simple blot-based detection of mono- and poly-ADP-ribosylated proteins. These tools can be expressed recombinantly in E. coli using commonly available agents and will help to investigate ADP-ribosylation systems and aid in drug discovery.

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Section: Discussionmentioning

confidence: 99%

A molecular toolbox for ADP-ribosyl binding proteins

Sowa

Galera‐Prat

Wazir

et al. 2021

Preprint

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“…PARP1 is activated by SSB to synthesize poly-ADP ribose (PAR) polymers at the damaged site [ 134 , 135 , 136 , 137 , 138 , 139 ]. Constitutive PARP1 activation can deplete intracellular NAD + levels, which can affect mitochondrial homeostasis, ROS production, DNA repair, and cell death [ 140 , 141 , 142 ].…”

Section: Crosstalk Between Ddr and Age-related Neurodegenerative Dmentioning

confidence: 99%

Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Gupta

You

SenGupta

et al. 2021

Biology

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Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

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“…Sinapine and tubeimoside‐1, the bioactive compounds in Sinapis semen and Bolbostemma paniculatum , exhibit reversed multidrug resistance and suppress metastasis in BC through NF‐κB activation [7,8]. The extract of Cinnamomum cassia demonstrates high anti‐proliferative activity against BC cells [9–11]. These cases support the view that YHD could be a promising TCM for the treatment of BC.…”

Section: Introductionmentioning

confidence: 87%

“…In clinical practice, estrogen receptor, aromatase, and poly adenosine 5′‐diphosphate‐ribose polymerase 1 (PARP1) are considered as important targets for the treatment of BC [11]. Among these targets, PARP1 has raised recent attention.…”

Section: Introductionmentioning

confidence: 99%

Development and evaluation of poly adenosine 5′‐diphosphate‐ribose polymerase 1 immobilization‐based receptor chromatography

Dou

Zhu

et al. 2020

J of Separation Science

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Yanghe decoction is a traditional Chinese medicine prescription and has been used for breast cancer treatment for many years. However, the effective ingredients in the decoction have not been identified. The expression of poly(ADP‐ribose) polymerase‐1 is highly related to breast cancer. Using poly(ADP‐ribose) polymerase‐1 as a probe, we expressed the haloalkane dehalogenase‐tagged protein in BL21(DE3) E. coli, immobilized it on hexachlorocaproic acid‐modified macroporous silica gel, and established a poly(ADP‐ribose) polymerase‐1 chromatographic model. The feasibility of the model was verified by testing the retention behaviors of five drugs on the protein column. We applied the model in screening the bioactive components in yanghe decoction. Rutin, liquiritin, and a compound ([M‐H]– 681.7) were identified to be the potential bioactive ingredients. We studied the binding property between rutin and poly(ADP‐ribose) polymerase‐1 by injection amount dependent method, competitive studies, and molecular docking. We found that rutin can bind to the protein through the typical inhibitor binding site of the protein. Therefore, the chromatographic model is a useful tool to screen bioactive compounds from traditional Chinese medicine. The method is fast, reliable, and applicable to other functional proteins that can screen the potential lead compounds for the treatment of the related diseases.

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Poly(ADP-Ribose) Glycohydrolase (PARG) vs. Poly(ADP-Ribose) Polymerase (PARP) – Function in Genome Maintenance and Relevance of Inhibitors for Anti-cancer Therapy

Cited by 67 publications

References 235 publications

A molecular toolbox for ADP-ribosyl binding proteins

A molecular toolbox for ADP-ribosyl binding proteins

Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Development and evaluation of poly adenosine 5′‐diphosphate‐ribose polymerase 1 immobilization‐based receptor chromatography

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