Richard Pomerantz, PhD
Assistant Professor, Biochemistry
Assistant Professor, Fels Institute for Cancer Research and Molecular Biology
Department of Biochemistry
Fels Institute for Cancer Research and Molecular Biology
DNA Repair, Genome Instability and Cancer
Genome instability is a hallmark of cancer cells and it is well established that defects in DNA repair pathways such as homologous recombination predispose to cancer. My laboratory is interested in understanding the underlying mechanisms of DNA repair in human cells and how proper genome maintenance reduces the risks of cancer. Understanding how proteins function within DNA repair pathways provides important insights into the etiology of certain cancers and is necessary for the development of novel cancer drugs.
Double-strand and single-strand breaks in DNA are repaired by a highly conserved pathway called homologous recombination which directs the replication machinery to copy sequence information from a homologous DNA donor. Homologous recombination is necessary for maintaining genome integrity and suppressing tumorigenesis. For example, mutations of important factors within this pathway such as tumor suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancers. BRCA2, which is considered a pro-recombination factor, loads RAD51 recombinase onto DNA which is necessary for the initiation of homologous recombination. Anti-recombination factors which dissociate RAD51 from DNA, however, are also important for genome maintenance. For example, defects in factors that dissociate recombination intermediates results in hyper-recombination and gross chromosomal rearrangements which are thought to promote cancer. Current research is focused on identifying anti-recombination factors in human cells and investigating their mechanisms and role in the regulation of DNA repair.
Most DNA repair processes including homologous recombination require the activity of DNA polymerases. Although several DNA polymerases have been discovered is human cells, many of their functions remain obscure. For example, DNA polymerase theta is a relatively newly discovered error-prone translesion DNA polymerase this is implicated in multiple DNA repair pathways including translesion synthesis, DNA double-strand break repair, base excision repair and interstrand crosslink repair. Importantly, DNA polymerase theta is significantly upregulated in 70% of breast cancers and such upregulation corresponds to a poor clinical outcome. Reducing the expression level of DNA polymerase theta has been shown to specifically sensitize cancer cells to radiation. Drugs that inhibit DNA polymerase theta may therefore be used as radiosensitizers and potentially increase the survival rate of breast cancer patients. Current research is focused on understanding the mechanism of action of DNA polymerase theta and identifying and developing small-molecule inhibitors of the polymerase for potential use in cancer therapy.