DNA polymerases; DNA replication; DNA damage and repair
Cells from all eukaryotic organisms must efficiently and accurately replicate their entire nuclear genome once, and only once, per cell cycle. This must occur while in the presence of continuous environmental and endogenous insults (e.g. chemical agents, ultraviolet light, oxidative stress, depletion of nucleotides) that can cause DNA base damage, DNA base-base mispairs, DNA strand breaks, and stalled replication forks. If left unrepaired, each of these insults can lead to mutagenesis or genome instability which can contribute to cancer and other human diseases.
In order to avoid genome instability and cancer, DNA polymerases play a central role in accurately replicating the genome and repairing damaged DNA. DNA Polymerase ε (Pol ε) plays important roles in DNA replication and the repair of damaged DNA, but is also unique among DNA polymerases in its involvement in control of cell cycle progression, chromatin remodeling and epigenetic inheritance.
Much is known about DNA polymerase ε from model organisms, largely from genetic and biochemical work done in budding yeast. In contrast, very little is known about how the human Pol ε replicates DNA, responds to damaged DNA at the replication fork, activates the checkpoint response, and contributes to overall genome stability. Additionally, the precise roles of Pol ε in both Base Excision Repair (BER) and Nucleotide Excision Repair (NER) remain unclear.
My lab is involved in precisely defining the roles that human Pol ε plays in DNA replication and DNA repair and its role in helping to maintain overall genome stability.