Joann Sweasy	Marlene Belfort

The three Rs— replication, recombination and repair— hold the key to DNA proliferation, stability and integrity. Alterations in these processes lead to developmental disorders and cancer, whereas exploitation of the three Rs holds the potential of reversing defects that lead to genetic abnormalities. The four exciting sessions in this theme will focus on genomic instability, chromosome dynamics and gene therapy, processing of non-B form DNA by the cell and RNA as a mediator of genome plasticity.

Genomic Instability

The first session, titled “Aberrant DNA Repair, Genomic Instability and Cancer,” will feature Richard D. Wood (University of Texas M. D. Anderson Cancer Center), who will describe work on several DNA polymerases that help human cells tolerate DNA damage. Results will be described using a mouse model deficient in DNA polymerase zeta. The enzyme is important in defending against chromosome instability, ultraviolet radiation sensitivity and mammary carcinogenesis. Recent information on the biochemical and cellular functions of two other DNA polymerases affecting genome stability, POLQ and POLN, also will be described.

Joann B. Sweasy (Yale University) will describe findings on the role of base excision repair as a tumor suppressor mechanism. Germ line variants in DNA polymerase beta alter the function of the enzyme and lead to genomic instability and cellular transformation. Pol beta is an enzyme that is important for filling in small gaps in DNA that result from the removal of DNA damage. Individuals who carry germ line variants in this gene may be at increased risk for cancer.

Bevin P. Engelward (Massachusetts Institute of Technology) will describe her work, which is focused on increasing our understanding of what causes genomic mutations, with an emphasis on how DNA repair protects the genome, and how our environment can put cells at risk for tumorigenic mutations. Of particular interest is crosstalk between base excision repair and homologous recombination, wherein one pathway can pressure the other. Engelward also will describe her development of novel technologies for detecting genetic changes, both in vitro and in vivo. These new tools have helped to shed new light on an old problem, yielding insights into the underlying mechanisms of exposure-induced genetic changes.