Detoxification: a novel function of BRCA1 in tumor suppression?
Detoxification: a novel function of BRCA1 in tumor suppression?
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DOI：
10.1093/toxsci/kfr089
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发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
Bae I
中科院分区：
文献类型：
--
作者：
Kang HJ;Hong YB;Kim HJ;Rodriguez OC;Nath RG;Tilli EM;Albanese C;Chung FL;Kwon SH;Bae I
我们的研究发现BRCA 1水平与苯并（a）芘（BaP）诱导的DNA加合物呈负相关。脉冲追踪实验表明，在BRCA 1敲除细胞中BaP诱导的DNA加合物的增加可能与BRCA 1在核苷酸切除修复活性中的功能无关;相反，它可能与其在调节转录调控中的功能有关。MCF-10A细胞中BRCA 1敲低显著减弱了BaP处理后CYP 1A 1的诱导，表明BRCA 1敲低细胞中BaP诱导的加合物的增加不是CYP 1A 1依赖性的。然而，我们的研究表明，BRCA 1缺陷细胞可能仍然能够通过调节包括CYP 1B 1在内的其他β-内酰胺酶来生物转化BaP。BRCA 1的敲除也严重影响了两种类型的尿苷二磷酸葡萄糖醛酸转移酶（UGT 1A 1和UGT 1A 9）和NRF 2的表达水平。这两种UGT都被称为BaP特异性解毒酶，NRF 2是抗氧化和解毒基因的主要调节因子。因此，我们得出结论，BRCA 1敲除细胞中BaP诱导的DNA加合物的量增加与其功能性解毒的丧失密切相关。染色质免疫沉淀分析显示，BRCA 1被募集到UGT 1A 1、UGT 1A 9和NRF 2的启动子/增强子序列。UGT 1A 1和UGT 1A 9表达的调节表明，BaP对DNA加合物的诱导直接受其表达水平的影响。最后，UGT、NRF 2或ARNT的过度表达显著降低BRCA 1缺陷细胞中BaP诱导的加合物的量。总体而言，我们的研究结果表明，BRCA 1保护细胞减少苯并（a）芘诱导的DNA加合物的量可能通过转录激活解毒基因的表达。
Our studies found that BRCA1 levels negatively correlate with DNA adducts induced by Benzo(a)pyrene (BaP). Pulse-chase experiments showed that the increase in BaP-induced DNA adducts in BRCA1 knockdown cells may not be associated with BRCA1’s function in nucleotide excision repair activity; rather, it may be associated with its function in modulating transcriptional regulation. BRCA1 knockdown in MCF-10A cells significantly attenuated the induction of CYP1A1 following BaP treatment indicating that the increase in BaP-induced adducts in BRCA1 knockdown cells is not CYP1A1 dependent. However, our study shows that BRCA1 defective cells may still be able to biotransform BaP by regulating other CYP enzymes, including CYP1B1. Knockdown of BRCA1 also severely affected the expression levels of two types of uridine diphosphate glucorunyltransferase (UGT1A1 and UGT1A9) and NRF2. Both UGTs are known as BaP-specific detoxification enzymes, and NRF2 is a master regulator of antioxidant and detoxification genes. Thus, we concluded that the increased amount of BaP-induced DNA adducts in BRCA1 knockdown cells is strongly associated with its loss of functional detoxification. Chromatin immunoprecipitation assay revealed that BRCA1 is recruited to the promoter/enhancer sequences of UGT1A1, UGT1A9, and NRF2. Regulation of UGT1A1 and UGT1A9 expression showed that the induction of DNA adducts by BaP is directly affected by their expression levels. Finally, overexpression of UGTs, NRF2, or ARNT significantly decreased the amount of BaP-induced adducts in BRCA1-deficient cells. Overall, our results suggest that BRCA1 protects cells by reducing the amount of BaP-induced DNA adducts possibly via transcriptional activation of detoxification gene expression.
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影响因子：
11.2
作者：
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通讯作者：
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