Research Interests

Human cells express multiple DNA polymerases that share the ability to utilize damaged DNA as a template for DNA replication, something our replicative high fidelity DNA polymerases cannot do. The fact that many anticancer drugs exert their main mechanism of action by damaging DNA brings forth the possibility that these additional polymerase activities could promote chemotherapeutic resistance. Our main objective is to understand at greater molecular detail how translesion DNA synthesis (TLS) polymerases allow cells to tolerate DNA damage and at the same time promote genomic stability. We are especially interested in studying the biological functions of DNA Polymerase Zeta (POLZ) and its partner TLS polymerase REV1. POLZ is the only TLS polymerases that leads to embryonic lethality in mice when its gene is deleted. Furthermore, cells lacking POLZ or REV1 display phenotypes very similar to those observed in human cells isolated from patients suffering from several hereditary cancer syndromes such as ataxia telangiectasia and Fanconi anemia when treated with ionizing radiation or interstrand DNA crosslinking agents, respectively. Our research is therefore focused on defining the biological functions of REV1 and POLZ in intercrosslink DNA repair and homologous recombination repair. To this end, we are currently studying whether structure specific endonucleases, mismatch repair proteins and the FANCD2/I heterodimer cooperate with POLZ and REV1 during these two important DNA repair processes (Figure to the left) by studying their protein-protein interactions. Our ultimate goal is to identify new strategies for overcoming tumor resistance to chemotherapeutic agents as well as understand with greater detail how cells cope with DNA damage and maintain DNA integrity.