Prof. Bevin P Engelward

The Engelward Lab studies DNA damage, repair, and homologous recombination. Cells are subjected to an onslaught of DNA lesions every day. One way that cells cope with DNA lesions is to use homology directed repair to exploit sequence information on sister chromatids or homologous chromosomes for the purpose of repairing DNA damage. Although this is a critically important defense against toxicity caused by DNA damaging agents, misalignments during homology directed repair can lead to sequence rearrangements that contribute to cancer (e.g., loss of heterozygosity and deletions). On the other hand, being unable to perform homology directed repair puts cells at risk of other types of tumorigenic rearrangements (e.g., chromosome aberrations). Thus, either too much or too little homology directed repair is potentially threatening to human health.

Homology directed repair is a critical system for maintaining genomic integrity. Indeed, we now know that many cancer-prone diseases are associated with defects in homology directed repair. For example, 55-75% of women who inherit mutations in the BRCA1 gene will get breast cancer before the age of 70, and we now know that BRCA1 is directly involved in homology directed repair. What types of DNA lesions cause homologous recombination in people? How does enzymatic processing of DNA lesions affect the likelihood that a lesion will lead to homologous recombination? The mission is to reveal how excision repair affects cellular susceptibility to homologous recombination in eukaryotes, and to develop novel tools for studying homologous recombination in mammals.

The first transgenic mice in which somatic cells that have undergone homologous recombination become fluorescent have been recently developed in the laboratory. The Fluorescent Yellow Direct Repeat (FYDR) mice are being used to compare recombination susceptibility among different cell types and to evaluate the effects of specific genetic defects on recombination susceptibility. Thus, the FYDR mice offer a novel approach for revealing the underlying causes of homologous recombination in mammals.