p50 (NF-κB1) is an effector protein in the cytotoxic response to DNA methylation damage

Mol Cell. 2011 Dec 9;44(5):785-96. doi: 10.1016/j.molcel.2011.09.026.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death
  • Cell Line, Tumor
  • DNA Damage*
  • DNA Methylation*
  • Humans
  • Mice
  • NF-kappa B p50 Subunit / antagonists & inhibitors
  • NF-kappa B p50 Subunit / deficiency
  • NF-kappa B p50 Subunit / metabolism*

Substances

  • NF-kappa B p50 Subunit