Differential involvement of the hMRE11/hRAD50/NBS1 complex, BRCA1 and MLH1 in NF-κB activation by camptothecin and X-ray

• Published in: Oncogene Vol. 22; no. 38; pp. 6090 - 6099
• Main Authors: HABRAKEN, Yvette, JOLOIS, Olivier, PIETTE, Jacques
• Format: Journal Article Web Resource
• Language: English
• Published: Basingstoke Nature Publishing 04.09.2003; Nature Publishing Group
• Subjects: ATLD; Biochemistry, biophysics & molecular biology; Biochimie, biophysique & biologie moléculaire; Biological and medical sciences; BRCA1; BRCA1 protein; Camptothecin; Cell cycle; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; DNA damage; double-strand breaks; Fundamental and applied biological sciences. Psychology; Homologous recombination; Human health sciences; Life sciences; MLH1 protein; MMR; Molecular and cellular biology; NBS; NF-kappa B; NF-κB protein; Oncologie; Oncology; Sciences de la santé humaine; Sciences du vivant; Signal transduction; Trimers; Double strand break; NF-κB; Regulation(control); MMR; ATLD; Activation; Molecular complex; X ray; BRCA1; double-strand breaks; NBS
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/sj.onc.1206893

Camptothecin (CPT) and X-ray (XR) generate double-strand breaks (DSB) that can be processed by homologous or nonhomologous recombination. We studied the participation of proteins involved in recombination pathways and cell cycle control in the signal transduction between DNA damage and NF-κB. Cells harbouring mutated NBS, hMRE11, BRCA1 or MLH1 were analysed. NBS- and hMRE11-deficient cells present a classical kinetic of NF-κB induction after camptothecin treatment. When DSB are generated by XR, NBS-deficient cells exhibit a delayed and strongly reduced level of NF-κB induction, whereas the hMRE11 mutated cells do not induce NF-κB at all. This indicates an important role of the hMRE11/hRAD50/NBS complex in the signal transduction initiated by XR. In HCC1937 cells that express a truncated version of BRCA1, XR induces a very rapid and transient NF-κB activation, whereas CPT leads to a delayed activation suggesting that BRCA1 modulates the transduction pathways in different manners after these two stresses. Finally, we found that a proficient MMR pathway is essential to the NF-κB activation after both CPT and XR. These results indicate that DSB originating from XR or CPT do not induce NF-κB in a unique way. MMR participates in both cascades, whereas the hMRE11/hRAD50/NBS trimer is specifically involved in the response elicited by XR.