Nitric Oxide: Genomic Instability And Synthetic Lethality.

Regardless of etiology, inflammatory conditions are characterized by overexpression of inducible nitric oxide synthase (iNOS) and overproduction of nitric oxide and reactive nitrogen species (NO/RNS) in epithelial and inflammatory cells at the site of carcinogenesis. NO/RNS produced in inflamed tissues can contribute to the process of carcinogenesis by different mechanisms. One of these mechanisms is NO-dependent stimulation of genomic instability by inhibiting of Breast Cancer type 1 Susceptibility protein (BRCA1) expression. Block of BRCA1 expression shifts DNA double-strand breaks (DSB) repair from error-free high-fidelity homologous recombination repair (HRR) to error-prone nonhomologous end joining (NHEJ). BRCA1 epigenetically block miRNA-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miRNA-155 promoter. The miRNA-155 is responsible for post-translational silencing of essential members of mismatch repair (MMR) core: MSH2, MSH6, and MLH1 proteins. They epigenetic inactivation induces DNA microsatellite instability (MSI). Recently, we demonstrated NO-dependent downregulation of MMR core proteins (MSH2, MSH6, and MLH1) through the ↓BRCA1/↑miRNA-155 signaling pathway. Hence, another NO-dependent mechanism of genomic instability is downregulation of MMR core proteins and stimulation of the DNA MSI. Loss or inhibition of Poly(ADP-ribose) polymerase 1 (PARP1) activity results in accumulation of DNA single-strand breaks, which are subsequently converted to DSB by the transcription machinery. In BRCA-positive cells, DSB are repaired by HRR, but they cannot be properly repaired in BRCA1-deficient cells, leading to genomic instability, chromosomal rearrangements, and cell death. Our data demonstrated that combination of NO-donors with PARP inhibitors significantly sensitized the BRCA1-positive cancer cells to DNA-damaging agents.