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Radiosensitization with an inhibitor of poly(ADP-ribose) glycohydrolase: A comparison with the PARP1/2/3 inhibitor olaparib

Gravells, P., Neale, J., Grant, E., Nathubhai, Amit, Smith, K.M., James, D.I. and Bryant, H.E. (2018) Radiosensitization with an inhibitor of poly(ADP-ribose) glycohydrolase: A comparison with the PARP1/2/3 inhibitor olaparib. DNA Repair, 61. pp. 25-36. ISSN 1568-7864

Item Type: Article


Upon DNA binding the poly(ADP-ribose) polymerase family of enzymes (PARPs) add multiple ADP-ribose
subunits to themselves and other acceptor proteins. Inhibitors of PARPs have become an exciting and real
prospect for monotherapy and as sensitizers to ionising radiation (IR). The action of PARPs are reversed by poly
(ADP-ribose) glycohydrolase (PARG). Until recently studies of PARG have been limited by the lack of an inhibitor.
Here, a first in class, specific, and cell permeable PARG inhibitor, PDD00017273, is shown to radiosensitize.
Further, PDD00017273 is compared with the PARP1/2/3 inhibitor olaparib. Both olaparib and
PDD00017273 altered the repair of IR-induced DNA damage, resulting in delayed resolution of RAD51 foci
compared with control cells. However, only PARG inhibition induced a rapid increase in IR-induced activation of
PRKDC (DNA-PK) and perturbed mitotic progression. This suggests that PARG has additional functions in the cell
compared with inhibition of PARP1/2/3, likely via reversal of tankyrase activity and/or that inhibiting the
removal of poly(ADP-ribose) (PAR) has a different consequence to inhibiting PAR addition. Overall, our data are
consistent with previous genetic findings, reveal new insights into the function of PAR metabolism following IR
and demonstrate for the first time the therapeutic potential of PARG inhibitors as radiosensitizing agents.

DNA Repair 61 2018 25-36.pdf - Published Version
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Depositing User: Amit Nathubhai


Item ID: 9785
Identification Number:
ISSN: 1568-7864
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Date Deposited: 10 Aug 2018 07:42
Last Modified: 04 Feb 2021 17:00


Author: P. Gravells
Author: J. Neale
Author: E. Grant
Author: Amit Nathubhai
Author: K.M. Smith
Author: D.I. James
Author: H.E. Bryant

University Divisions

Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences


Sciences > Biomedical Sciences

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