Bioenergetic metabolites regulate base excision repair-dependent cell death in response to DNA damage.
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.
Tang
Jiang-bo
JB
Hillman Cancer Center, University of Pittsburgh Cancer Institute, Research Pavilion, Suite 2.6a, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, USA.
Goellner
Eva M
EM
Wang
Xiao-hong
XH
Trivedi
Ram N
RN
St Croix
Claudette M
CM
Jelezcova
Elena
E
Svilar
David
D
Brown
Ashley R
AR
Sobol
Robert W
RW
D017209:Apoptosis / Q000502:physiology; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D004249:DNA Damage / Q000502:physiology*; D019951:DNA Polymerase beta / Q000172:deficiency / Q000235:genetics; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases; D019951:DNA Polymerase beta