Two decades into the twenty-first century, a confluence of breakthrough technologies wielded at the molecular level is presenting biologists with unique opportunities to unravel the complexities of the cellular world. CRISPR/Cas9 allows gene knock-outs, knock-ins, and single-base editing at chromosomal loci. RNA-based tools such as siRNA, antisense oligos, and morpholinos can be used to silence expression of specific genes. Meanwhile, protein knockdown tools that draw inspiration from natural regulatory mechanisms and facilitate elimination of native or degron-tagged proteins from cells are rapidly emerging. The acute and reversible reduction in protein levels enabled by these methods allows for precise determination of loss-of-function phenotypes free from secondary effects or compensatory adaptation that can confound nucleic-acid-based methods that involve slow depletion or permanent loss of a protein. In this Review, we summarize the ingenious ways biologists have exploited natural mechanisms for protein degradation to direct the elimination of specific proteins at will. This has led to advancements not only in basic research but also in the therapeutic space with the introduction of PROTACs into clinical trials for cancer patients.

中文翻译：

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利用蛋白水解的力量来靶向蛋白质灭活。

进入二十一世纪的二十年间，在分子水平上所应用的突破性技术的融合为生物学家提供了揭开细胞世界复杂性的独特机会。CRISPR / Cas9允许在染色体基因座上进行基因敲除，敲入和单碱基编辑。基于RNA的工具（例如siRNA，反义寡核苷酸和吗啉代）可用于沉默特定基因的表达。同时，从自然调节机制中汲取灵感并促进从细胞中消除天然或地格隆标签的蛋白质的蛋白质敲除工具正在迅速出现。这些方法可以使蛋白质水平急剧且可逆地降低，从而可以精确确定功能丧失的表型，而没有次级效应或补偿性适应，而后者可能使基于核酸的方法（包括蛋白质的缓慢消耗或永久性损失）混淆。在这篇综述中，我们总结了生物学家利用蛋白质降解的自然机制来指导随意清除特定蛋白质的巧妙方法。通过将PROTAC引入癌症患者的临床试验中，不仅在基础研究领域而且在治疗领域也取得了进步。我们总结了生物学家利用蛋白质降解的自然机制来直接消除特定蛋白质的巧妙方法。通过将PROTAC引入癌症患者的临床试验中，不仅在基础研究领域而且在治疗领域也取得了进步。我们总结了生物学家利用蛋白质降解的自然机制来直接消除特定蛋白质的巧妙方法。通过将PROTAC引入癌症患者的临床试验中，不仅在基础研究领域而且在治疗领域也取得了进步。