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

Oncogene. 2003 Sep 4;22(38):6090-9. doi: 10.1038/sj.onc.1206893.

Abstract

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-kappaB. Cells harbouring mutated NBS, hMRE11, BRCA1 or MLH1 were analysed. NBS- and hMRE11-deficient cells present a classical kinetic of NF-kappaB induction after camptothecin treatment. When DSB are generated by XR, NBS-deficient cells exhibit a delayed and strongly reduced level of NF-kappaB induction, whereas the hMRE11 mutated cells do not induce NF-kappaB 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-kappaB 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-kappaB activation after both CPT and XR. These results indicate that DSB originating from XR or CPT do not induce NF-kappaB in a unique way. MMR participates in both cascades, whereas the hMRE11/hRAD50/NBS trimer is specifically involved in the response elicited by XR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Anhydride Hydrolases
  • Adaptor Proteins, Signal Transducing
  • BRCA1 Protein / drug effects
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism*
  • BRCA1 Protein / radiation effects
  • Camptothecin / pharmacology*
  • Carrier Proteins
  • Cell Cycle Proteins / drug effects
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / radiation effects
  • DNA / drug effects
  • DNA / radiation effects
  • DNA Damage / physiology
  • DNA Repair Enzymes*
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / radiation effects
  • Enzyme Inhibitors / pharmacology
  • HeLa Cells / drug effects
  • HeLa Cells / radiation effects
  • Humans
  • MRE11 Homologue Protein
  • Macromolecular Substances
  • MutL Protein Homolog 1
  • Mutation
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism*
  • NF-kappa B / radiation effects
  • Neoplasm Proteins / drug effects
  • Neoplasm Proteins / metabolism*
  • Neoplasm Proteins / radiation effects
  • Nuclear Proteins / drug effects
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / radiation effects
  • Radiation, Ionizing
  • Signal Transduction
  • X-Rays*

Substances

  • Adaptor Proteins, Signal Transducing
  • BRCA1 Protein
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • MLH1 protein, human
  • MRE11 protein, human
  • Macromolecular Substances
  • NBN protein, human
  • NF-kappa B
  • Neoplasm Proteins
  • Nuclear Proteins
  • xeroderma pigmentosum group F protein
  • DNA
  • MRE11 Homologue Protein
  • Acid Anhydride Hydrolases
  • Rad50 protein, human
  • MutL Protein Homolog 1
  • DNA Repair Enzymes
  • Camptothecin