Transposon molecular domestication and the evolution of the RAG recombinase
发布时间 :2019-06-12  阅读次数 :9403


主讲人简介:张宇航博士,现任耶鲁大学医学院博士后,2004年本科毕业于吉林大学,2007年于吉林大学获得博士学位,2011年于中科院生化与细胞研究所获得博士学位。在Nature, Cell等杂志发表研究论文






Domestication of a transposon (a DNA sequence that can change its position in a genome) to give rise to the RAG1–RAG2 recombinase (RAG) and V(D)J recombination, which produces the diverse repertoire of antibodies and T cell receptors, was a pivotal event in the evolution of the adaptive immune system of jawed vertebrates. The evolutionary adaptations that transformed the ancestral RAG transposase into a RAG recombinase with appropriately regulated DNA cleavage and transposition activities are not understood. Here, beginning with cryo-electron microscopy structures of the amphioxus ProtoRAG transposase (an evolutionary relative of RAG), we identify amino acid residues and domains the acquisition or loss of which underpins the propensity of RAG for coupled cleavage, its preference for asymmetric DNA substrates and its inability to perform transposition in cells. In particular, we identify two adaptations specific to jawed-vertebrates—arginine 848 in RAG1 and an acidic region in RAG2—that together suppress RAG-mediated transposition more than 1,000-fold. Our findings reveal a two-tiered mechanism for the suppression of RAG-mediated transposition, illuminate the evolution of V(D)J recombination and provide insight into the principles that govern the molecular domestication of transposons.