2017年10月4日,英国《自然》在线发表美国耶鲁大学、哥伦比亚大学、科罗拉多州立大学的研究报告,发现乳腺癌易感基因1(BRCA1)突变的致病机制。
肿瘤抑制复合物BRCA1-BARD1通过同源重组功能发挥修复DNA双链断裂的作用,BRCA1-BARD1在此过程中促进DNA末端核酸水解切除作用,以产生招募另一种肿瘤抑制复合物BRCA2-PALB2和重组酶RAD51的单链模板。
BARD1:BRCA1相关RING结构域蛋白(BRCA1-Associated Really Interesting New Gene Domain)
PALB2:BRCA2配偶蛋白和定位蛋白(Partner And Localizer of BRCA2)
RAD51:真核生物体内蛋白质,对同源重组发挥主要作用,参与搜寻同源部位与DNA的配对过程。
该研究通过分析纯化的野生型和突变型BRCA1-BARD1,证实BRCA1和BARD1均可与DNA结合,并与RAD51相互作用,BRCA1-BARD1可增强RAD51的重组酶活性。BRCA1-BARD1促进突触复合物装配,突触复合物是RAD51介导DNA接头形成的必需中间物。该研究证实BRCA1和BARD1对于RAD51激活必不可少。值得注意的是,突变型BRCA1-BARD1与RAD51的相互作用减弱,从而破坏DNA接头形成,并妨碍细胞同源重组和DNA修复。上述研究结果揭示了BRCA1-BARD1对同源重组后期的作用,这是肿瘤抑制复合物的特性,可被用以癌症靶向疗法。
因此,该研究发现了导致BRCA1丧失DNA修复和抗肿瘤能力的分子机制。BRCA1与BARD1的相互作用是DNA修复的必要因素,BRCA1对DNA修复和肿瘤抑制发挥作用,是证实癌症风险遗传的首个证据,能够加强对女性乳腺癌风险的了解,有助于提高医生预测患者癌症风险的专业能力。确定BRCA相关DNA修复途径机制将有助于未来研发更有效治疗乳腺癌的药物,并有助于提前发现乳腺癌高风险女性。
Nature. 2017 Oct 4. [Epub ahead of print]
BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing.
Zhao W, Steinfeld JB, Liang F, Chen X, Maranon DG, Jian Ma C, Kwon Y, Rao T, Wang W, Sheng C, Song X, Deng Y, Jimenez-Sainz J, Lu L, Jensen RB, Xiong Y, Kupfer GM, Wiese C, Greene EC, Sung P.
Yale University School of Medicine, New Haven, Connecticut, USA; Columbia University, New York, New York, USA; Colorado State University, Fort Collins, Colorado, USA; Yale School of Public Health, New Haven, Connecticut, USA.
The tumour suppressor complex BRCA1-BARD1 functions in the repair of DNA double-stranded breaks by homologous recombination. During this process, BRCA1-BARD1 facilitates the nucleolytic resection of DNA ends to generate a single-stranded template for the recruitment of another tumour suppressor complex, BRCA2-PALB2, and the recombinase RAD51. Here, by examining purified wild-type and mutant BRCA1-BARD1, we show that both BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1-BARD1 enhances the recombinase activity of RAD51. Mechanistically, BRCA1-BARD1 promotes the assembly of the synaptic complex, an essential intermediate in RAD51-mediated DNA joint formation. We provide evidence that BRCA1 and BARD1 are indispensable for RAD51 stimulation. Notably, BRCA1-BARD1 mutants with weakened RAD51 interactions show compromised DNA joint formation and impaired mediation of homologous recombination and DNA repair in cells. Our results identify a late role of BRCA1-BARD1 in homologous recombination, an attribute of the tumour suppressor complex that could be targeted in cancer therapy.
PMID: 28976962
DOI: 10.1038/nature24060
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