title: DNA damage-induced cytotoxicity is mediated by the cooperative interaction of phospho-NF-κB p50 and a single nucleotide in the κB-site.
abstract: Phosphorylation of the NF-κB subunit, p50, is necessary for cytotoxicity in response to DNA methylation damage. Here, we demonstrate that serine 329 phosphorylation regulates the interaction of p50 with specific NF-κB binding elements based on the identity of a single κB-site nucleotide. Specifically, S329 phosphorylation reduces the affinity of p50 for κB-sites that have a cytosine (C) at the -1 position without affecting binding to sequences with a -1 adenine. The differential interaction between phospho-p50 and the -1 base regulates the downstream transcriptional response and underlies the inhibition of anti-apoptotic gene expression following DNA damage. In genes with multiple κB-sites, the presence of a single -1C κB-site enables inhibition of NF-κB-dependent activity. The data suggest that interaction between phospho-p50 and the -1 κB nucleotide facilitates cytotoxicity in response to DNA damage. Moreover, although conservation of the entire κB-site sequence is not seen across species, the identity of the -1 nt in critical anti-apoptotic genes is conserved such that the overall response to DNA damage is maintained.
authors.affiliation: Section of Neurosurgery, Department of Surgery, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Clayton D
authors.initials: CD
authors.lastname: Crawley
authors.forename: David R
authors.initials: DR
authors.lastname: Raleigh
authors.forename: Shijun
authors.initials: S
authors.lastname: Kang
authors.forename: David J
authors.initials: DJ
authors.lastname: Voce
authors.forename: Adam M
authors.initials: AM
authors.lastname: Schmitt
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: Bakhtiar
authors.initials: B
authors.lastname: Yamini
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D005786:Gene Expression Regulation; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000737:chemistry / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012694:Serine / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009711:Nucleotides; D012694:Serine; D004247:DNA