Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland.
Department of Surgical Oncology, Nicolaus Copernicus Memorial Regional Cancer Center, 93-513 Lodz, Poland.
Int J Mol Sci. 2020 Jan 29;21(3):870. doi: 10.3390/ijms21030870.
A fraction of breast cancer cases are associated with mutations in the (BRCA1 DNA repair associated, breast cancer type 1 susceptibility protein) gene, whose mutated product may disrupt the repair of DNA double-strand breaks as BRCA1 is directly involved in the homologous recombination repair of such DNA damage. However, BRCA1 can stimulate nucleotide excision repair (NER), the most versatile system of DNA repair processing a broad spectrum of substrates and playing an important role in the maintenance of genome stability. NER removes carcinogenic adducts of diol-epoxy derivatives of benzo[α]pyrene that may play a role in breast cancer pathogenesis as their accumulation is observed in breast cancer patients. NER deficiency was postulated to be intrinsic in stage I of sporadic breast cancer. BRCA1 also interacts with GADD45A (growth arrest and DNA damage-inducible protein GADD45 alpha) that may target NER machinery to actively demethylate genome sites in order to change the expression of genes that may be important in breast cancer. Therefore, the interaction between BRCA1 and GADD45 may play a role in breast cancer pathogenesis through the stimulation of NER, increasing the genomic stability, removing carcinogenic adducts, and the local active demethylation of genes important for cancer transformation.
乳腺癌病例中有一小部分与 （BRCA1 与 DNA 修复相关的乳腺癌 1 型易感性蛋白）基因的突变有关，其突变产物可能破坏 DNA 双链断裂的修复，因为 BRCA1 直接参与这种 DNA 损伤的同源重组修复。然而，BRCA1 可以刺激核苷酸切除修复（NER），这是一种最通用的 DNA 修复系统，能够处理广泛的底物，并在维持基因组稳定性方面发挥重要作用。NER 去除苯并[a]芘二醇-环氧衍生物的致癌加合物，这些加合物可能在乳腺癌发病机制中起作用，因为在乳腺癌患者中观察到它们的积累。NER 缺陷被假定为散发性乳腺癌 I 期的内在缺陷。BRCA1 还与 GADD45A（生长停滞和 DNA 损伤诱导蛋白 GADD45alpha）相互作用，GADD45A 可能将 NER 机制靶向到基因组位点，以主动去甲基化，从而改变可能对乳腺癌重要的基因的表达。因此，BRCA1 和 GADD45 之间的相互作用可能通过刺激 NER 、增加基因组稳定性、去除致癌加合物以及对癌症转化重要的基因的局部活性去甲基化在乳腺癌发病机制中发挥作用。
