Journal
MOLECULAR CELL
Volume 44, Issue 5, Pages 785-796Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2011.09.026
Keywords
-
Categories
Funding
- Novartis Oncology through the CALGB Foundation
- NIH [1R01CA136937, R01CA111423]
- Center for Radiation Therapy
- Ludwig Center for Metastasis Research
Ask authors/readers for more resources
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-kappa B 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-kappa B-regulated antiapoptotic gene expression. Inhibition of NF-kappa B 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-kappa B DNA binding. Expression of an unphosphorylatable p50 mutant blocks inhibition of NF-kappa B-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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available