BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability.
BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability.
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DOI：
10.1158/0008-5472.can-13-2611
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发表时间：
2014-05-15
期刊：
影响因子：
11.2
通讯作者：
Harkin DP
中科院分区：
文献类型：
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作者：
Savage KI;Matchett KB;Barros EM;Cooper KM;Irwin GW;Gorski JJ;Orr KS;Vohhodina J;Kavanagh JN;Madden AF;Powell A;Manti L;McDade SS;Park BH;Prise KM;McIntosh SA;Salto-Tellez M;Richard DJ;Elliott CT;Harkin DP
BRCA 1的生殖系突变使携带者易患乳腺癌和卵巢癌。BRCA 1通过在DNA修复、细胞周期阻滞和转录控制中发挥关键作用来维持基因组稳定性。一个主要的问题是，既然BRCA 1在所有细胞类型中都具有重要功能，那么为什么BRCA 1缺失或突变主要会导致雌激素调节组织中的肿瘤。在这里，我们报告说，雌激素和雌激素代谢物可以导致DNA双链断裂（DSB）在雌激素受体-α阴性乳腺细胞和BRCA 1是必需的，以修复这些DSB，以防止代谢物诱导的基因组不稳定性。我们发现BRCA 1还通过抑制乳腺细胞中的雌激素代谢酶（如CYP 1A 1）的转录来调节雌激素代谢和代谢物介导的DNA损伤。最后，我们使用了一个带有杂合BRCA 1致病性突变的敲入人类细胞模型来显示BRCA 1单倍不足如何影响这些过程。我们的研究结果为为什么BRCA 1突变驱动雌激素调节组织中肿瘤的形成提供了关键的新见解，尽管BRCA 1在所有细胞类型的DNA修复中发挥着普遍作用。
Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell cycle arrest and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here we report that estrogen and estrogen metabolites can cause DNA double strand breaks (DSB) in estrogen receptor-α negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolising enzymes, such as CYP1A1, in breast cells. Lastly, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumours in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types.