美国哥伦比亚大学Samuel H. Sternberg小组发现，从转座子中分离出来的TnpB同源物是RNA引导的转录因子。该研究于2024年6月26日在线发表于国际一流学术期刊《自然》。

研究人员试图验证一个假设，即TnpB核酸酶也可能被重新用于CRISPR-Cas适应性免疫之外的新的、意想不到的功能。研究人员利用系统发生学、结构预测、比较基因组学和功能测试，发现了可编程转录因子的多个独立成因事件，并将其命名为TnpB样核酸酶抑制因子（TldR）。这些蛋白利用天然存在的向导RNA，特异性地靶向基因组中的保守启动子区域，从而在一种类似于人类发明的CRISPR干扰技术的机制中实现强效基因抑制。

研究人员聚焦于广泛存在于肠杆菌科细菌中的TldR支系，发现噬菌体利用TldR和邻近编码的噬菌体基因的联合作用来改变宿主鞭毛组装的表达和组成，这种转变有可能影响运动性、噬菌体敏感性和宿主免疫力。总之，这项工作展示了通过转座子编码基因的反复适应而实现的各种分子创新，并揭示了各种RNA引导的转录因子的演化轨迹。

据悉，转座子编码的tnpB和iscB基因编码RNA引导的DNA核酸酶，它们通过有针对性的DNA切割和同源重组促进自身的自私传播。这些广泛存在的基因家族在演化过程中被反复驯化，导致了包括Cas9和Cas12在内的多种CRISPR相关核酸酶的出现。

附：英文原文

Title: TnpB homologues exapted from transposons are RNA-guided transcription factors

Author: Wiegand, Tanner, Hoffmann, Florian T., Walker, Matt W. G., Tang, Stephen, Richard, Egill, Le, Hoang C., Meers, Chance, Sternberg, Samuel H.

Issue&Volume: 2024-06-26

Abstract: Transposon-encoded tnpB and iscB genes encode RNA-guided DNA nucleases that promote their own selfish spread through targeted DNA cleavage and homologous recombination1,2,3,4. These widespread gene families were repeatedly domesticated over evolutionary timescales, leading to the emergence of diverse CRISPR-associated nucleases including Cas9 and Cas12 (refs. 5,6). We set out to test the hypothesis that TnpB nucleases may have also been repurposed for novel, unexpected functions other than CRISPR–Cas adaptive immunity. Here, using phylogenetics, structural predictions, comparative genomics and functional assays, we uncover multiple independent genesis events of programmable transcription factors, which we name TnpB-like nuclease-dead repressors (TldRs). These proteins use naturally occurring guide RNAs to specifically target conserved promoter regions of the genome, leading to potent gene repression in a mechanism akin to CRISPR interference technologies invented by humans7. Focusing on a TldR clade found broadly in Enterobacteriaceae, we discover that bacteriophages exploit the combined action of TldR and an adjacently encoded phage gene to alter the expression and composition of the host flagellar assembly, a transformation with the potential to impact motility8, phage susceptibility9, and host immunity10. Collectively, this work showcases the diverse molecular innovations that were enabled through repeated exaptation of transposon-encoded genes, and reveals the evolutionary trajectory of diverse RNA-guided transcription factors.

DOI: 10.1038/s41586-024-07598-4

Source: https://www.nature.com/articles/s41586-024-07598-4