title: p50 (NF-κB1) is an effector protein in the cytotoxic response to DNA methylation damage.
abstract: The functional significance of the signaling pathway induced by O(6)-methylguanine (O(6)-MeG) lesions is poorly understood. Here, we identify the p50 subunit of NF-κB as a central target in the response to O(6)-MeG and demonstrate that p50 is required for S(N)1-methylator-induced cytotoxicity. In response to S(N)1-methylation, p50 facilitates the inhibition of NF-κB-regulated antiapoptotic gene expression. Inhibition of NF-κB activity is noted to be an S phase-specific phenomenon that requires the formation of O(6)-MeG:T mismatches. Chk1 associates with p50 following S(N)1-methylation, and phosphorylation of p50 by Chk1 results in the inhibition of NF-κB DNA binding. Expression of an unphosphorylatable p50 mutant blocks inhibition of NF-κB-regulated antiapoptotic gene expression and attenuates S(N)1-methylator-induced cytotoxicity. While O(6)-MeG:T-induced, p50-dependent signaling is not sufficient to induce cell death, this pathway sensitizes cells to the cytotoxic effects of DNA breaks.
authors.affiliation: Department of Surgery, Section of Neurosurgery, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Schmitt
authors.forename: Clayton D
authors.initials: CD
authors.lastname: Crawley
authors.forename: Shijune
authors.initials: S
authors.lastname: Kang
authors.forename: David R
authors.initials: DR
authors.lastname: Raleigh
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yu
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Wahlstrom
authors.forename: David J
authors.initials: DJ
authors.lastname: Voce
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Darga
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: Bakhtiar
authors.initials: B
authors.lastname: Yamini
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D004249:DNA Damage; D019175:DNA Methylation; D006801:Humans; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*
chemical_list: D052002:NF-kappa B p50 Subunit