Nitric oxide-dependent downregulation of BRCA1 expression promotes genetic instability.
Nitric oxide-dependent downregulation of BRCA1 expression promotes genetic instability.
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DOI：
10.1158/0008-5472.can-12-3270
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发表时间：
2013-01-15
期刊：
影响因子：
11.2
通讯作者：
Yakovlev VA
中科院分区：
文献类型：
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作者：
Yakovlev VA
一氧化氮（NO）和活性氮（RNS）水平的升高可能与炎症与癌症的发生、促进和进展有关。传统上，这种联系被认为是由NO/RNS在产生DNA损伤中的作用介导的。然而，这种损伤也会刺激DNA修复反应，随后阻断细胞增殖和凋亡，从而阻止NO/ rns产生的突变的积累。为了解决这个难题，我在这里描述了理解NO/RNS诱变的另一种机制。中等NO/RNS浓度刺激突变不是通过直接产生DNA损伤，而是通过间接改变DNA修复和基因组稳定因子的活性而不影响细胞增殖。与炎症生理相关浓度的NO/RNS刺激PP2A活性，导致RBL2去磷酸化，其在细胞核中积累，形成RBL2/E2F4复合物。RBL2/E2F4的形成反过来导致BRCA1启动子的占据从含有激活因子E2F1的复合物转变为含有抑制因子E2F4的复合物，从而下调BRCA1的表达。通过抑制BRCA1的表达，NO/RNS降低了细胞通过同源重组修复修复DNA双链断裂的能力，增加了易出错的非同源末端连接（NHEJ）的参与。总之，NO/RNS通过抑制brca1表达和将DNA修复从高保真转向易出错机制来刺激遗传不稳定性。
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 physiological 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.