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In vivo transposition mediated by V(D)J recombinase in human T lymphocytes

By Terri L. Messier, J.Patrick O’Neill, Sai-Mei Hou, Janice A. Nicklas and Barry A. Finette

Abstract

The rearrangement of immunoglobulin (Ig) and T-cell receptor (TCR) genes in lymphocytes by V(D)J recombinase is essential for immunological diversity in humans. These DNA rearrangements involve cleavage by the RAG1 and RAG2 (RAG1/2) recombinase enzymes at recombination signal sequences (RSS). This reaction generates two products, cleaved signal ends and coding ends. Coding ends are ligated by non-homologous end-joining proteins to form a functional Ig or TCR gene product, while the signal ends form a signal joint. In vitro studies have demonstrated that RAG1/2 are capable of mediating the transposition of cleaved signal ends into non-specific sites of a target DNA molecule. However, to date, in vivo transposition of signal ends has not been demonstrated. We present evidence of in vivo inter-chromosomal transposition in humans mediated by V(D)J recombinase. T-cell isolates were shown to contain TCRα signal ends from chromosome 14 inserted into the X-linked hypo xanthine–guanine phosphoribosyl transferase locus, resulting in gene inactivation. These findings implicate V(D)J recombinase-mediated transposition as a mutagenic mechanism capable of deleterious genetic rearrangements in humans

Topics: Articles
Publisher: Oxford University Press
Year: 2003
DOI identifier: 10.1093/emboj/cdg137
OAI identifier: oai:pubmedcentral.nih.gov:151080
Provided by: PubMed Central
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