Discovery of an Active RAG Transposon Illuminates the Origins of V(D)J Recombination.
Co-option of RAG1 and RAG2 for antigen receptor gene assembly by V(D)J recombination was a crucial event in the evolution of jawed vertebrate adaptive immunity. RAG1/2 are proposed to have arisen from a transposable element, but definitive evidence for this is lacking. Here, we report the discovery of ProtoRAG, a DNA transposon family from lancelets, the most basal extant chordates. A typical ProtoRAG is flanked by 5-bp target site duplications and a pair of terminal inverted repeats (TIRs) resembling V(D)J recombination signal sequences. Between the TIRs reside tail-to-tail-oriented, intron-containing RAG1-like and RAG2-like genes. We demonstrate that ProtoRAG was recently active in the lancelet germline and that the lancelet RAG1/2-like proteins can mediate TIR-dependent transposon excision, host DNA recombination, transposition, and low-efficiency TIR rejoining using reaction mechanisms similar to those used by vertebrate RAGs. We propose that ProtoRAG represents a molecular "living fossil" of the long-sought RAG transposon.
State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, People's Republic of China.
Shengfeng
S
Huang
State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, People's Republic of China.
Xin
X
Tao
State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, People's Republic of China.
Shaochun
S
Yuan
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA.
Yuhang
Y
Zhang
State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, People's Republic of China.
Peiyi
P
Li
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA.
Helen A
HA
Beilinson
State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, People's Republic of China.
Ya
Y
Zhang
State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, People's Republic of China.
Wenjuan
W
Yu
CNRS, Centrale Marseille, I2M UMR 7373, Equipe Evolution Biologique et Modélisation, Aix-Marseille Université, 13284 Marseille, France.
Pierre
P
Pontarotti
CNRS, UMR 7232, Biologie Integrative des Organismes Marins (BIOM), Observatoire Océanologique de Banyuls-sur-Mer, Banyuls-sur-Mer, Université Pierre et Marie Curie, Université Paris 6, 75005 Paris, France.
Hector
H
Escriva
CNRS, UMR 7232, Biologie Integrative des Organismes Marins (BIOM), Observatoire Océanologique de Banyuls-sur-Mer, Banyuls-sur-Mer, Université Pierre et Marie Curie, Université Paris 6, 75005 Paris, France.
Yann
Y
Le Petillon
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China.
Xiaolong
X
Liu
State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, People's Republic of China.
Shangwu
S
Chen
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, 295 Congress Avenue, New Haven, CT 06511, USA.
David G
DG
Schatz
State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, People's Republic of China; Beijing University of Chinese Medicine, Dong San Huan Road, Chao-yang District, Beijing 100029, People's Republic of China. Electronic address: lssxal@mail.sysu.edu.cn.
Anlong
A
Xu
D000818:Animals; D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins; D019143:Evolution, Molecular; D018398:Homeodomain Proteins; D064175:Lancelets / Q000235:genetics*; D020079:Terminal Repeat Sequences; D060152:V(D)J Recombination
D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein