Chromosome fragility and translocations in lymphocytes

Rockefeller University, New York NY

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Abstract

? DESCRIPTION (provided by applicant): Chromosome fragility and translocations in lymphocytes Summary DNA double-strand breaks pose a particularly serious threat to genome integrity, as they predispose to chromosome rearrangements, which can lead to cancer. Recurrent chromosome translocations and deletions are found across a multitude of malignancies (such as lymphomas, leukemias, and carcinomas of the lung, breast and prostate) and involve hundreds of cancer genes (1, 2). However, little is known about the molecular mechanisms governing these aberrant DNA recombinations, and particularly about the cause of fragility of specific genes. Under physiologic conditions, programmed DNA breaks are obligate intermediates during the assembly and diversification reactions of antibody genes. The RAG1/2 recombinase breaks DNA in developing lymphocytes during the assembly of the variable gene segments (V(D)J recombination). In activated B cells, Activation-Induced cytidine Deaminase (AID) causes DNA breaks while altering antibody effector functions during class switch recombination (CSR). Tumors of lymphocytes (lymphomas) often bear hallmark oncogenic translocations involving antibody genes, and the physiologically occurring DNA breaks at these loci are thought to be a predisposing factor (3, 4). However, the source of DNA damage at the oncogene partners involved in these translocations is less clear. B lymphocytes are rapidly dividing cells that proliferate in distinct bursts: first during B cell development in the bone marrow at a time when RAG1/2 is expressed, and later in germinal centers when AID is expressed. RAG1/2, AID and DNA replication are all associated with DNA damage (5, 6). AID causes DNA breaks at the c-myc oncogene and lymphoma-associated chromosome translocations (7, 8). Moreover, AID causes collateral DNA damage at hundreds of other genes in activated B cells, and genome- wide DNA breaks by AID can lead to chromosome deletions and translocations, including some that are found in human B cell lymphoma (9, 10). In contrast, despite a large body of circumstantial evidence, the parameters by which RAG1/2 is mistargeted to generate lymphomagenic aberrations remain not well understood. In two specific aims we propose to test the hypothesis that RAG1/2 damages the B cell genome by mechanisms that are not limited to its action at RSS sites. First, we will examine the DNA damage by RAG1/2 to the genome of primary developing B cells. Second, we will define the landscape of RAG1/2 induced chromosome rearrangements. The long-term goal of the proposed research is to obtain a comprehensive molecular understanding of the genesis of chromosome translocations in B lymphocytes.