Mechanisms of genome mutating processes involved in immune function and cancer
Our research is centered around understanding processes that mutate the human and/or viral genomes. Protection of genomes against mutations and damage is a biological tenet. Since the genomic DNA sequence of an organism is its very definition, protecting the fidelity of this sequence is of paramount importance. Consequently all organisms have multiple redundant molecular pathways that vigilantly monitor and maintain their genomic integrity. The sole exception to this general rule occurs in lymphocytes which are specialized immune cells. These white blood cells purposefully damage their own genomic DNA. They have developed mechanisms that mutate their genome and also physically break their chromosomes in order to alter specific genes involved in an immune response. In so doing, they are able to adapt and become more effective during an immune response. Lymphocytes also express DNA mutating enzymes that target the genomes of retroviruses (e.g. HIV) which infect them, with the goal of restricting the replication of these viruses.
On the one hand, these genome mutating processes exist to boost and protect the immune system. On the other hand, these same processes may be targeted to the wrong genes and cause mutations and/or chromosomal breaks leading to the transformation of immune cells into lymphoma or leukemias. Furthermore, these processes can be erroneously activated in cells of non-immune tissues and lead to cancers. These include breast cancer, ovarian cancer, lung cancer, prostate cancer, liver cancer, and others. In addition, these DNA mutating processes often continue operating in tumors resulting in increased aggressiveness, escape from recognition by the immune system as well as resistance to treatment. Along the same line, the genome mutating processes that mutate viral genomes in order to protect lymphocytes can also contribute to mutations in the viral genomes that favor the virus rather than the host.
Our broad areas of investigation include:
1) Elucidating the molecular mechanisms of genome mutating enzymes
2) Understanding the regulation of the activity of these enzymes in healthy cells and tumors
3) Investigating the manner in which their activity influences immune function and cancer in physiological settings
4) Mapping the evolution and biological activities of DNA mutating processes across species