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Verdun Lab

Molecular basis of genome integrity

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Investigator / Contact Person Ramiro Verdun

Research

The goal of this laboratory is to increase our knowledge in these molecular mechanisms used by our cells to keep the integrity of our DNA.

One of the model system that we study to understand how the different DNA repair mechanisms maintain genome stability are telomeres. The natural ends of the linear chromosomes, represent a problem in the control of genome stability. An exposed telomere could be confused with a chromosome internal break, and the cell will respond by repairing it, leading to chromosome fusions. When cells with fused chromosomes progress through mitosis, breakage-fusion cycles occur, causing genome instability. Therefore, it is vital for a cell to distinguish the natural chromosome ends from DNA breaks.

Another model system that we use is antibody class switch recombination (CSR). The recognition and elimination of pathogens by the immune system via antibodies depends critically on the recombination of DNA breaks in the immunoglobulin heavy chain (Igh) locus during class switching. These DNA breaks are initiated by activation-induced cytosine deaminase (AID) at distal G-rich repetitive DNA regions in the Igh locus. Although after stimulation AID is mostly targeted to the Igh locus, it also mutates non-Igh genes including proto-oncogenes as a side effect. This 'off-target' activity of AID initiates chromosome translocations between Igh and non-Igh genes that are associated hematological malignancies.

The best characterized of these is the Igh-cmyc translocation which places c-myc under the control of regulatory elements of Igh and is associated with Burkitt's and a subset of diffuse large B cell lymphomas. Although in recent years several pathways involved in CSR have been characterized, current knowledge of how these pathways are controlled during this process remains rudimentary, severely hampering the development of therapies for controlling humoral immune response in pathogenic states. Thus, unraveling the mechanisms that regulate DNA repair pathways during CSR is of high priority in modern medicine.