Joined: May 2002
it's been known for several years now that the RAG proteins can mediate transposition in vitro, providing pretty strong evidence for the theory that the RAG genes evolved from an ancient transposase (though not the only evidence). skeptics of the theory claim that the ability to catalyze a reaction in vitro does not necessarily mean that it does so in vivo, or more to the point, that it did so. there is some basis to this argument. additionally, it has been theorized that RAG-mediated transposition in vivo could be a source of mutation. the paper below not only demonstrates that RAG proteins can act as transposases, but also that the activity is possibly tumorigenic:
|In vivo transposition mediated by V(D)J recombinase in human T lymphocytes |
Terri L. Messier, J.Patrick O’Neill, Sai-Mei Hou, Janice A. Nicklas and Barry A. Finette
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 TCR(alpha) 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.
Edited by rafe gutman on Mar. 21 2003,16:23