Nature子刊：上海科技大学季泉江团队发现超小型基因编辑系统Cas12p，并揭示其激活开关

Core Viewpoint - The article discusses a novel mechanism of activation for a new class of phage-derived Cas12 nucleases, known as Cas12p, which utilizes bacterial thioredoxin (TrxA) for its activation and DNA cleavage [4][12]. Group 1: Research Findings - A new type of ultra-small Cas12 nuclease, Cas12p, has been identified, which consists of 500-700 amino acids and activates its DNA cutting activity by "hijacking" the bacterial thioredoxin [4]. - The research team established an efficient process for discovering new variants of the V-type CRISPR-Cas systems from metagenomic data, indicating that many unknown variants likely exist in nature [8][11]. - Structural analysis using cryo-electron microscopy revealed that Cas12p interacts closely with an endogenous bacterial protein, confirming TrxA as its specific binding partner [12]. Group 2: Mechanism of Action - The study elucidates the molecular basis of TrxA's activation of Cas12p, where TrxA binding induces conformational changes in Cas12p, allowing it to recognize sgRNA-DNA hybrids and activate its nuclease activity [12]. - Genetic experiments demonstrated that knocking out the trxA gene results in the loss of Cas12p's genomic interference capability, while reintroducing trxA fully restores its activity, confirming TrxA as an essential "activation switch" for Cas12p [12]. Group 3: Implications for Gene Editing - Cas12p's compact size lowers the delivery barrier for gene therapy, and the revealed "host factor-assisted activation" mechanism offers new directions for optimizing the efficiency and activity of gene editing tools [12]. - By introducing specific auxiliary factors and modifying related domains, there is potential to enhance the activity of other ultra-small Cas proteins and create "molecular switches" for precise control of gene editing, leading to the development of highly active and safe gene editing systems [12].