title: Nitric oxide-dependent downregulation of BRCA1 expression promotes genetic instability.
abstract: Elevated levels of nitric oxide (NO) and reactive nitrogen species (RNS) may link inflammation to the initiation, promotion, and progression of cancer. Traditionally, this link has been thought to be mediated by the effects of NO/RNS in generating DNA damage. However, this damage also stimulates DNA repair responses with subsequent blocks to cell proliferation and apoptosis, thereby preventing accumulation of NO/RNS-generated mutations. In addressing this conundrum, I describe here an alternative mechanism for understanding mutagenesis by NO/RNS. Moderate NO/RNS concentrations stimulated mutagenesis not directly by generating DNA damage but indirectly by modifying the activities of DNA repair and genome stability factors without affecting cell proliferation. NO/RNS at concentrations physiologically relevant to inflammation stimulated PP2A activity, leading to dephosphorylation of RBL2, its accumulation in the nucleus, and formation of RBL2/E2F4 complexes. RBL2/E2F4 formation in turn led to a shift in BRCA1 promoter occupancy from complexes containing activator E2F1 to complexes containing repressor E2F4, downregulating BRCA1 expression. By inhibiting BRCA1 expression, NO/RNS thereby reduces the ability of cells to repair DNA double-strand breaks through homologous recombination repair, increasing the involvement of error-prone nonhomologous end joining (NHEJ). In summary, NO/RNS stimulates genetic instability by inhibiting BRCA1 expression and shifting DNA repair from high fidelity to error-prone mechanisms.
authors.affiliation: Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298, USA. vayakovlev@vcu.edu
authors.forename: Vasily A
authors.initials: VA
authors.lastname: Yakovlev
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004260:DNA Repair; D015536:Down-Regulation; D042822:Genomic Instability; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D009569:Nitric Oxide / Q000378:metabolism*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D059767:Recombinational DNA Repair
chemical_list: D019313:BRCA1 Protein; D026361:Reactive Nitrogen Species; D009569:Nitric Oxide