Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
J Biol Chem. 2010 Jun 18;285(25):19092-105. doi: 10.1074/jbc.M110.104430. Epub 2010 Feb 25.
Inactivation of the breast cancer susceptibility gene BRCA1 plays a significant role in the development of a subset of breast cancers, although the major tumor suppressor function of this gene remains unclear. Previously, we showed that BRCA1 induces antioxidant-response gene expression and protects cells against oxidative stress. We now report that BRCA1 stimulates the base excision repair pathway, a major mechanism for the repair of oxidized DNA, by stimulating the activity of key base excision repair (BER) enzymes, including 8-oxoguanine DNA glycosylase (OGG1), the DNA glycosylase NTH1, and the apurinic endonuclease redox factor 1/apurinic endonuclease 1 (REF1/APE1), in human breast carcinoma cells. The increase in BER enzyme activity appears to be due, primarily, to an increase in enzyme expression. The ability of BRCA1 to stimulate the expression of the three BER enzymes and to enhance NTH1 promoter activity was dependent upon the octamer-binding transcription factor OCT1. Finally, we found that OGG1, NTH1, and REF1/APE1 each contribute to the BRCA1 protection against oxidative stress due to hydrogen peroxide and that hydrogen peroxide stimulates the expression of BRCA1 and the three BER enzymes. These findings identify a novel mechanism through which BRCA1 may regulate the repair of oxidative DNA damage.
BRCA1 乳腺癌易感基因失活在部分乳腺癌的发生发展中起着重要作用，尽管该基因的主要肿瘤抑制功能仍不清楚。先前，我们已经表明 BRCA1 诱导抗氧化反应基因的表达，并保护细胞免受氧化应激的影响。我们现在报告 BRCA1 通过刺激关键碱基切除修复（BER）酶的活性，包括 8-氧鸟嘌呤 DNA 糖苷酶（OGG1）、DNA 糖苷酶 NTH1 和无嘌呤内切核酸酶还原因子 1/无嘌呤内切核酸酶 1（REF1/APE1），刺激氧化 DNA 的碱基切除修复途径，这是修复氧化 DNA 的主要机制，在人乳腺癌细胞中。BER 酶活性的增加似乎主要归因于酶表达的增加。BRCA1 刺激三种 BER 酶的表达和增强 NTH1 启动子活性的能力依赖于八聚体结合转录因子 OCT1。最后，我们发现 OGG1、NTH1 和 REF1/APE1 均有助于 BRCA1 抵抗过氧化氢引起的氧化应激，并且过氧化氢刺激 BRCA1 和三种 BER 酶的表达。这些发现确定了 BRCA1 可能调节氧化 DNA 损伤修复的新机制。
