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

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    Authors
    Gravells, P
    Neale, J
    Grant, E
    Nathubhai, A
    Smith, Kate M
    James, Dominic I
    Bryant, H
    Affiliation
    Academic Unit of Molecular Oncology, Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Beech Hill Road, Sheffield
    Issue Date
    2017-11-22
    
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    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.
    Citation
    Radiosensitization with an inhibitor of poly(ADP-ribose) glycohydrolase: A comparison with the PARP1/2/3 inhibitor olaparib. 2017, 61:25-36 DNA Repair (Amst.)
    Journal
    DNA repair
    URI
    http://hdl.handle.net/10541/620713
    DOI
    10.1016/j.dnarep.2017.11.004
    PubMed ID
    29179156
    Type
    Article
    Language
    en
    ISSN
    1568-7856
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.dnarep.2017.11.004
    Scopus Count
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    All Paterson Institute for Cancer Research

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