MERIT Award Recipient: Michael R. Lieber, M.D., Ph.D.
Human V(D)J Recombinase in Neoplastic and Primary Cells
All cancers initiate with some type of DNA alteration. Chromosomal translocations are one such type of DNA alteration, and in cancer, this typically increases the expression of a gene that helps the cell proliferate so that it can become a cancer. In order for a chromosomal translocation to occur, a break in the DNA must occur, and this is usually a break in both strands of the duplex (i.e., a double-strand DNA break). Such breaks can occur randomly in the DNA due to free radical DNA damage, for example. However, many of the breaks occur very consistently within specific regions of the genome. Some of these breaks are due to mistaken recognition of the DNA sequence by certain enzymes that normally function elsewhere in the genome, and this is the basis for inception of certain T-cell acute lymphoblastic leukemias. However, the most common chromosomal fragile site in lymphoid malignancies is at the bcl-2 major breakpoint region (Mbr), which constitutes only 150 base pairs of the 6 billion base pair genome. The bcl-2 Mbr breakage occurs in all follicular lymphomas, which accounts for about 40% of all non-Hodgkin lymphomas. We are trying to determine why this 150 bp region is distinctly fragile. This project is focused on understanding the structural reasons for the DNA fragility at this important site and understanding the enzymes that cut this fragile region. Once we understand this one fragile region, the information gained may shed light on other chromosomal fragile sites in cancer.