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

Polly Gravells, James Neale, Emma Grant, Amit Nathubhai, Kate M. Smith, Dominic I. James, Helen E. Bryant

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)25-36
Number of pages12
JournalDNA Repair
Volume61
Early online date22 Nov 2017
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • Homologous recombination
  • Non-homologous end-joining
  • PARG
  • PARP
  • Radiosensitization
  • Tankyrase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Radiosensitization with an inhibitor of poly(ADP-ribose) glycohydrolase: A comparison with the PARP1/2/3 inhibitor olaparib'. Together they form a unique fingerprint.

  • Cite this

    Gravells, P., Neale, J., Grant, E., Nathubhai, A., Smith, K. M., James, D. I., & 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, 25-36. https://doi.org/10.1016/j.dnarep.2017.11.004