Harrision, D., Gravells, P., Thompson, R. et al. (1 more author) (2020) Poly(ADP-Ribose) glycohydrolase (PARG) vs. poly(ADP-Ribose) polymerase (PARP) – function in genome maintenance and relevance of inhibitors for anti-cancer therapy. Frontiers in Molecular Biosciences, 7. 191. ISSN 2296-889X
Abstract
Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that catalyze the addition of poly(ADP-ribose) (PAR) subunits onto themselves and other acceptor proteins. PARPs are known to function in a large range of cellular processes including DNA repair, DNA replication, transcription and modulation of chromatin structure. Inhibition of PARP holds great potential for therapy, especially in cancer. Several PARP1/2/3 inhibitors (PARPi) have had success in treating ovarian, breast and prostate tumors harboring defects in the homologous recombination (HR) DNA repair pathway, especially BRCA1/2 mutated tumors. However, treatment is limited to specific sub-groups of patients and resistance can occur, limiting the use of PARPi. Poly(ADP-ribose) glycohydrolase (PARG) reverses the action of PARP enzymes, hydrolysing the ribose-ribose bonds present in poly(ADP-ribose). Like PARPs, PARG is involved in DNA replication and repair and PARG depleted/inhibited cells show increased sensitivity to DNA damaging agents. They also display an accumulation of perturbed replication intermediates which can lead to synthetic lethality in certain contexts. In addition, PARG is thought to play an important role in preventing the accumulation of cytoplasmic PAR and therefore parthanatos, a caspase-independent PAR-mediated type of cell death. In contrast to PARP, the therapeutic potential of PARG has been largely ignored. However, several recent papers have demonstrated the exciting possibilities that inhibitors of this enzyme may have for cancer treatment, both as single agents and in combination with cytotoxic drugs and radiotherapy. This article discusses what is known about the functions of PARP and PARG and the potential future implications of pharmacological inhibition in anti-cancer therapy.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 Harrision, Gravells, Thompson and Bryant. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
Keywords: | poly(ADP-ribose)polymerase (PARP); poly(ADP-ribose)glycohydrolase (PARG); synthetic lethality; chemosensitization; radiosensitization; cancer |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Metabolism (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 02 Oct 2020 10:09 |
Last Modified: | 02 Oct 2020 10:09 |
Status: | Published |
Publisher: | Frontiers Media SA |
Refereed: | Yes |
Identification Number: | 10.3389/fmolb.2020.00191 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:165491 |