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Mol Cancer Res. 2010 Jan;8(1):67-79. doi: 10.1158/1541-7786.MCR-09-0411. Epub 2010 Jan 12.

Bioenergetic metabolites regulate base excision repair-dependent cell death in response to DNA damage.

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Hillman Cancer Center, University of Pittsburgh Cancer Institute, Research Pavilion, Suite 2.6a, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, USA.


Base excision repair (BER) protein expression is important for resistance to DNA damage-induced cytotoxicity. Conversely, BER imbalance [DNA polymerase beta (Polbeta) deficiency or repair inhibition] enhances cytotoxicity of radiation and chemotherapeutic DNA-damaging agents. Whereas inhibition of critical steps in the BER pathway result in the accumulation of cytotoxic DNA double-strand breaks, we report that DNA damage-induced cytotoxicity due to deficiency in the BER protein Polbeta triggers cell death dependent on poly(ADP-ribose) (PAR) polymerase activation yet independent of PAR-mediated apoptosis-inducing factor nuclear translocation or PAR glycohydrolase, suggesting that cytotoxicity is not from PAR or PAR catabolite signaling. Cell death is rescued by the NAD(+) metabolite beta-nicotinamide mononucleotide and is synergistic with inhibition of NAD(+) biosynthesis, showing that DNA damage-induced cytotoxicity mediated via BER inhibition is primarily dependent on cellular metabolite bioavailability. We offer a mechanistic justification for the elevated alkylation-induced cytotoxicity of Polbeta-deficient cells, suggesting a linkage between DNA repair, cell survival, and cellular bioenergetics.

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