Processes shed light on how DNA recombination mechanisms are related

Peter W. Atkinson, a University of California, Riverside professor of entomology and member of the university’s Institute for Integrative Genome Biology, is part of a team that has linked the movement of small pieces of DNA, known as transposable elements, to a process called V(D)J recombination that produces the genetic diversity responsible for the production of antibodies. This will help scientists understand the mixing and matching of DNA in organisms and the role this mixing plays in healthy and diseased cells.

Nancy L. Craig from the Howard Hughes Medical Institute and Department of Molecular Biology & Genetics at Johns Hopkins Medical Institute led the team, which published its findings in this week’s issue of the journal Nature, in a paper titled Transposition of hAT elements links transposable elements and V(D)J recombination. Also on the team were Liqin Zhou and Rupak Mitra from Johns Hopkins, and Alison Burgess Hickman and Fred Dyda from the Laboratory of Molecular Biology at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md.

“These functional and comparative studies link the movement of transposable elements and V(D)J recombination. This outcome has implications for understanding transposable element movement in all organisms as well as the role that transpositional type recombination mechanisms have in chromosomal rearrangements of both healthy and diseased cells,” Atkinson said. “Of growing interest is the role that some of these rearrangements may play in the genesis of some cancers.”

Transposable elements, or small pieces of DNA that can move around within and sometimes between genomes, move through a process called transposition. Transposable elements are classified by their mechanisms of transposition. V(D)J recombination is the process by which antigen receptor genes, which encode antibodies, are created in specialized blood cells called B lymphocytes. This regulated process that involves local chromosomal rearrangements such as deletions and inversions is responsible for generating the diversity of antibodies produced by these cells.

For many years these two processes– transposable element transposition and V(D)J recombination – were thought to have some similarities and therefore may have evolved from an ancestral recombination system.

“No one, however, could establish this link. The work described in this paper establishes this link,” said Atkinson.

The paper describes the mechanism by which a member of one family of transposable elements actually moves. This element is called Hermes and was discovered by Atkinson and David O'Brochta of the University of Maryland about a decade ago. The element comes from the housefly and is a member of the hAT family of transposable elements that includes the Ac element of maize, which Geneticist Barbara McClintock, of the Carnegie Institution’s Cold Harbor Laboratory in New York, discovered many decades ago.

The paper shows that, like many transposable elements, Hermes cuts away from donor DNA via double strand breaks and that the ends of the element then join to the target DNA. Unlike other transposable elements, hairpin intermediates are formed at the ends of the donor DNA rather than on the ends of the element itself. This also occurs during V(D)J recombination.

In addition, comparison of the secondary structure of the Hermes transposase (the enzyme that mediates Hermes element transposition) with the RAG1 recombinase (the enzyme that mediates V(D)J recombination) and the transposases of some retroviruses shows clear similarities between these recombination enzymes.