The two faces of endogenous DNA editing enzymes: Promoting gene mutations as well as genome repair

 

Type B lymphocytes are a specific type of white blood cell within our immune system. They produce and export antibodies which seek out, attach to, and neutralize microbes and toxins. A unique way that B lymphocytes boost their antibody response is through making changes in the genes that encode for antibodies. These genetic changes in B lymphocytes are carried out by AID, an enzyme that alters the sequence of antibody genes, leading to improved antibodies and hence improved immunity.

However, AID activity is often misdirected to the wrong genes, or mis-expressed in the wrong cell types. This results in genetic mutations that can transform healthy cells into cancers. As a result, AID is now recognized as a leading cause of aggressive lymphoma/leukaemia and several solid tissue tumours. Furthermore, continued AID activity in cancer cells increases their ability to mutate and therefore become resistant to therapeutic approaches. Thus, the current scientific belief is that AID causes mutations to the genome of cells which in turn results in causing and/or exacerbating cancer.

Strong preliminary data hints at the possibility of a completely new aspect of AID activity: DNA damaged by external sources such as radiation can itself attract AID and this may serve to correct/repair some of the damage. The aim of this project is to study the extent and mechanisms of this effect, and investigate whether it represents a possible pathway by which cancer cells can evade or become resistant to chemotherapy or radiation therapy, since many cancer therapies work through inducing DNA damage. The results of this project may have important implications for cancer treatment strategies.

The project is led in Canada by Memorial University of Newfoundland in collaboration with the Hebrew University of Jerusalem (Israel) and researchers from Pakistan and India. It was selected and approved for funding through the second research competition of the Joint Canada-Israel Health Research Program, which is a partnership between Canada’s International Development Research Centre, the Canadian Institutes for Health Research, the Israel Science Foundation and the Azrieli Foundation. This seven-year, $35M Canadian-Israeli effort draws on the unique scientific strengths of both countries and facilitates networking opportunities with peers from Africa, Asia, and Latin America. Projects include a plan for integrating researchers from low- and middle-income countries that will establish long-term scientific relationships.