NAD + bioavailability mediates PARG inhibition-induced replication arrest, intra S-phase checkpoint and apoptosis in glioma stem cells.

Autor:	Li J; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., M Saville K; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Ibrahim M; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Zeng X; Biomedical Mass Spectrometry Center, University of Pittsburgh Schools of the Health Sciences, Pittsburgh, PA 15213, USA., McClellan S; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Angajala A; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Beiser A; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Andrews JF; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Sun M; Biomedical Mass Spectrometry Center, University of Pittsburgh Schools of the Health Sciences, Pittsburgh, PA 15213, USA., Koczor CA; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Clark J; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Hayat F; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Makarov MV; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Wilk A; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Yates NA; Biomedical Mass Spectrometry Center, University of Pittsburgh Schools of the Health Sciences, Pittsburgh, PA 15213, USA., Migaud ME; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Sobol RW; Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
Jazyk:	angličtina
Zdroj:	NAR cancer [NAR Cancer] 2021 Nov 17; Vol. 3 (4), pp. zcab044. Date of Electronic Publication: 2021 Nov 17 (Print Publication: 2021).
DOI:	10.1093/narcan/zcab044
Abstrakt:	Elevated expression of the DNA damage response proteins PARP1 and poly(ADP-ribose) glycohydrolase (PARG) in glioma stem cells (GSCs) suggests that glioma may be a unique target for PARG inhibitors (PARGi). While PARGi-induced cell death is achieved when combined with ionizing radiation, as a single agent PARG inhibitors appear to be mostly cytostatic. Supplementation with the NAD + precursor dihydronicotinamide riboside (NRH) rapidly increased NAD + levels in GSCs and glioma cells, inducing PARP1 activation and mild suppression of replication fork progression. Administration of NRH+PARGi triggers hyperaccumulation of poly(ADP-ribose) (PAR), intra S-phase arrest and apoptosis in GSCs but minimal PAR induction or cytotoxicity in normal astrocytes. PAR accumulation is regulated by select PARP1- and PAR-interacting proteins. The involvement of XRCC1 highlights the base excision repair pathway in responding to replication stress while enhanced interaction of PARP1 with PCNA, RPA and ORC2 upon PAR accumulation implicates replication associated PARP1 activation and assembly with pre-replication complex proteins upon initiation of replication arrest, the intra S-phase checkpoint and the onset of apoptosis. (© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer.)
Databáze:	MEDLINE
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