p53 suppresses hyper-recombination by modulating BRCA1 function.
p53 suppresses hyper-recombination by modulating BRCA1 function.
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p53 通过调节 BRCA1 功能抑制超重组
DOI：
10.1016/j.dnarep.2015.06.005
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发表时间：
2015-09
期刊：
影响因子：
3.8
通讯作者：
Feng Z
中科院分区：
文献类型：
--
作者：
Dong C;Zhang F;Luo Y;Wang H;Zhao X;Guo G;Powell SN;Feng Z
p53和BRCA1都是肿瘤抑制因子，参与许多细胞过程，包括细胞周期阻滞、细胞凋亡、转录调控和DNA损伤修复。一些研究表明，BRCA1和p53的关联是参与细胞复制和DNA修复途径的基因转录调控所必需的。然而，这两种蛋白在DNA修复分子机制中的关系尚不清楚。因此，我们试图确定p53和BRCA1在DNA修复中是否存在功能联系。首先，我们将质粒重组底物pDR-GFP整合到乳腺癌细胞系MCF7的基因组中，通过HPV-E6诱导p53失活和p53敲低两种独立的细胞模型，证明了p53抑制rad51介导的超重组修复。我们的研究进一步表明，在DNA修复响应中，p53通过转录调控机制抑制BRCA1过功能介导同源重组（homologous recombination， HR）。由于发现p53和BRCA1存在于一个蛋白复合体中，说明这两种蛋白可能在转录后水平上存在关联。此外，有缺陷的p53诱导的超重组与细胞的辐射抗性和染色体稳定性有关，这有力地支持了p53参与抑制超重组，从而导致基因稳定性和细胞功能对DNA损伤的反应。此外，我们发现p53缺失通过恢复HR和染色体稳定性来挽救BRCA1缺陷，这表明p53也独立于BRCA1参与HR抑制。因此，我们的数据表明，p53通过依赖brca1和不依赖brca1的机制参与抑制重组，在转录水平和可能的转录后水平上，p53的抑制和brca1的促进在调控HR活性方面存在功能联系。
Both p53 and BRCA1 are tumor suppressors and are involved in a number of cellular processes including cell cycle arrest, apoptosis, transcriptional regulation, and DNA damage repair. Some studies have suggested that the association of BRCA1 and p53 is required for transcriptional regulation of genes involved in cell replication and DNA repair pathways. However, the relationship between the two proteins in molecular mechanisms of DNA repair is still not clear. Therefore, we sought to determine whether there is a functional link between p53 and BRCA1 in DNA repair. Firstly, using a plasmid recombination substrate, pDR-GFP, integrated into the genome of breast cancer cell line MCF7, we have demonstrated that p53 suppressed Rad51-mediated hyper-recombinational repair by two independent cell models of HPV-E6 induced p53 inactivation and p53 knockdown assay. Our study further indicated that p53 mediated homologous recombination (HR) through inhibiting BRCA1 over-function via mechanism of transcription regulation in response to DNA repair. Since it was found p53 and BRCA1 existed in a protein complex, indicating both proteins may be associated at post-transcriptional level. Moreover, defective p53-induced hyper-recombination was associated with cell radioresistance and chromosomal stability, strongly supporting the involvement of p53 in the inhibition of hyper-recombination, which led to genetic stability and cellular function in response to DNA damage. In addition, it was found that p53 loss rescued BRCA1 deficiency via recovering HR and chromosomal stability, suggesting that p53 is also involved in the HR-inhibition independently of BRCA1. Thus, our data indicated that p53 was involved in inhibiting recombination by both BRCA1-dependent and -independent mechanisms, and there is a functional link between p53-suppression and BRCA1-promotion in regulation of HR activity at transcription level and possible post-transcription level.