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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

Abstract

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.

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More Information

Depositing User: Amit Nathubhai

Identifiers

Item ID: 9785
Identification Number: https://doi.org/10.1016/j.dnarep.2017.11.004
ISSN: 1568-7864
URI: http://sure.sunderland.ac.uk/id/eprint/9785
Official URL: https://www.sciencedirect.com/science/article/pii/...

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Catalogue record

Date Deposited: 10 Aug 2018 07:42
Last Modified: 04 Feb 2021 17:00

Contributors

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

Subjects

Sciences > Biomedical Sciences

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