V(D)J recombination: pre-cleavage complex and 12/23 rule

  • Cortes, , Patricia (PI)

Project Details

Description

Studies in my laboratory are directed to gain a better understanding of antigen receptor gene

assembly, also known as V(D)J recombination, a reaction that is central for the generation of a

normal and diverse immune system. Antigen receptor gene assembly is directed by consensus

DNA sequences and the complete reaction can be divided in recognition and cleavage of the

DNA followed by processing and joining of the cleaved DNA ends. The early steps of

recognition and cleavage of the DNA sequences are mediated by the products of the

recombination activating genes 1 and 2 (RAG1 and RAG2). Inactivation of these genes in

either human or mouse results in a severe combined immunodeficiency. Despite rapid

progress in understanding the early steps of V(D)J recombination, the molecular mechanisms

that govern regulated cleavage, the focus of study in this proposal, processing and joining of

the ends remain largely obscure. So far, only five proteins have been implicated in the joining

process: DNA-PKcs, Ku, XRCC4, ligase IV and Artemis, which are also essential for DNA

double-strand break repair. Moreover, it has been shown that mutations and/or deletions in

human ligase IV and Artemis produce severe immunodeficiencies, genomic instability and

cancer. Mice deficient in DNA-PKcs, Ku, XRCC4, ligase IV and Artemis are severely

immunodeficient and prompt to B-cell leukemias.

V(D)J recombination normally yields products that are mean to produce immunoglobulins and

T cell receptors. However, it has become clear that aberrant recombination events, which occur

at a significant rate, could give rise to translocations. In most cases, these translocations are

the cause of lymphomas and leukemias, some of the most common types of human cancer.

The proposed studies, which focus on the understanding of the molecular mechanism of

regulated cleavage, constitute an important step towards understanding the etiology of major

diseases of the immune system. It is predicted that all the information gained through our

studies will not only increase our understanding of the reaction but it will also open new

strategies for therapeutic information and implementation of prevention and treatment against

diseases of the immune system.

StatusFinished
Effective start/end date1/07/0430/06/08

Funding

  • American Cancer Society: $714,000.00

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