Specific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase

Gravells, Polly; Grant, Emma K.; Smith, Kate; James, Dominic I.; Bryant, Helen E.

doi:10.1016/j.dnarep.2017.02.010

Cited by 68 publications

(83 citation statements)

References 66 publications

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“…Future efforts in the development of small molecule inhibitors will hopefully produce new probes to study the (patho-)physiological roles of these fascinating enzymes as well as lead to new drugs with therapeutic applications. The potential of such an approach was highlighted over recent years with the development of PARG inhibitors finding their application in cancer therapy (James et al 2016;Gravells et al 2017;Waszkowycz et al 2018).…”

Section: Discussionmentioning

confidence: 99%

(ADP-ribosyl)hydrolases: structure, function, and biology

2020

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ADP-ribosylation is an intricate and versatile posttranslational modification involved in the regulation of a vast variety of cellular processes in all kingdoms of life. Its complexity derives from the varied range of different chemical linkages, including to several amino acid side chains as well as nucleic acids termini and bases, it can adopt. In this review, we provide an overview of the different families of (ADP-ribosyl)hydrolases. We discuss their molecular functions, physiological roles, and influence on human health and disease. Together, the accumulated data support the increasingly compelling view that (ADP-ribosyl)hydrolases are a vital element within ADP-ribosyl signaling pathways and they hold the potential for novel therapeutic approaches as well as a deeper understanding of ADP-ribosylation as a whole.

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Section: Discussionmentioning

confidence: 99%

(ADP-ribosyl)hydrolases: structure, function, and biology

2020

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“…Furthermore, the MRN complex is frequently found absent in patients with epithelial ovarian cancer (11). MRN functional disruption may be a synthetic lethal combination with poly(ADP-ribose) glycohydrolase (PARG) inhibition (12) providing a possible strategy to target MRN-defective cancers by inhibition of PARG, whose structure is defined (13). However, upregulation of RAD50 increases cellular radioresistance, and knockdown sensitizes some cancer cells to radiation, suggesting MRN may be a target for precision medicine (14).…”

Section: Introductionmentioning

confidence: 99%

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

Syed

Tainer

2018

Annu. Rev. Biochem.

306

336

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Genomic instability in disease and its fidelity in health depend on the DNA damage response (DDR), regulated in part from the complex of meiotic recombination 11 homolog 1 (MRE11), ATP-binding cassette–ATPase (RAD50), and phosphopeptide-binding Nijmegen breakage syndrome protein 1 (NBS1). The MRE11–RAD50–NBS1 (MRN) complex forms a multifunctional DDR machine. Within its network assemblies, MRN is the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection. MRN can interfere with cancer therapy and is an attractive target for precision medicine. Its conformations change the paradigm whereby kinases initiate damage sensing. Delineated results reveal kinase activation, posttranslational targeting, functional scaffolding, conformations storing binding energy and en-abling access, interactions with hub proteins such as replication protein A (RPA), and distinct networks at DNA breaks and forks. MRN biochemistry provides prototypic insights into how it initiates, implements, and regulates multifunctional responses to genomic stress.

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“…A strong case can be made for the importance of the biomedical implications of the inhibition of PARG in the field of cancer therapy. For example, the absence or inhibition of PARG has been shown to arrest the metastasis of cancer cells in the human colon and in murine models, the death of BRCA-2 tumor cells (487,488), and cell death of homologous repair-deficient tumor cells (489). PARG silencing led to a reduction in PARP expression and a decrease in signaling through the phosphatidylinositol (PI) 3-kinase/Akt pathway, mediated through a reduction in NF-B (487).…”

Section: Role Of Pargmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Brady

Goel

Johnson

2019

Microbiol Mol Biol Rev

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SUMMARYThe literature review presented here details recent research involving members of the poly(ADP-ribose) polymerase (PARP) family of proteins. Among the 17 recognized members of the family, the human enzyme PARP1 is the most extensively studied, resulting in a number of known biological and metabolic roles. This review is focused on the roles played by PARP enzymes in host-pathogen interactions and in diseases with an associated inflammatory response. In mammalian cells, several PARPs have specific roles in the antiviral response; this is perhaps best illustrated by PARP13, also termed the zinc finger antiviral protein (ZAP). Plant stress responses and immunity are also regulated by poly(ADP-ribosyl)ation. PARPs promote inflammatory responses by stimulating proinflammatory signal transduction pathways that lead to the expression of cytokines and cell adhesion molecules. Hence, PARP inhibitors show promise in the treatment of inflammatory disorders and conditions with an inflammatory component, such as diabetes, arthritis, and stroke. These functions are correlated with the biophysical characteristics of PARP family enzymes. This work is important in providing a comprehensive understanding of the molecular basis of pathogenesis and host responses, as well as in the identification of inhibitors. This is important because the identification of inhibitors has been shown to be effective in arresting the progression of disease.

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Specific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase

Cited by 68 publications

References 66 publications

(ADP-ribosyl)hydrolases: structure, function, and biology

(ADP-ribosyl)hydrolases: structure, function, and biology

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

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