DNA repair and genomic stability
Paull's research is focused on the repair of DNA double-strand breaks in eukaryotic cells and the consequences of this repair on genomic stability and oncogenic transformation.
In recent years it has become apparent that intricate molecular systems guard the genome against DNA damage and rearrangement during the course of the cell cycle and in response to exogenous agents. Several components of these systems have been implicated as tumor suppressors in mammalian organisms, thus establishing DNA repair factors as major targets in the progression from normal to unregulated cell growth. Current studies in the lab involve the biochemical activities of a complex of proteins, Mrell/Rad50/Nbs1 (M/R/N), which are critical components in the repair of DNA double-strand breaks. Much of the ongoing research involves the regulatory interactions between the M/R/N complex and other proteins known to be involved in the homologous recombination and non-homologous end-joining pathways. These also include regulatory kinases such as ATM, ATR and DNA-dependent protein kinase, as well as the products of the tumor suppressor genes BRCA1 and BRCA2. Paull's primary goal is to achieve an understanding of the mechanistic roles of these factors and how they cooperate to guard the cell against genetic rearrangement. In addition to DNA repair, the M/R/N complex is essential for telomere maintenance and for the initiation of meiotic recombination, both processes which involve specialized double-strand breaks. Currently, the model of M/R/N action within the cell is one in which the activities of the complex have varied outcomes depending on the context of the double-strand break and the molecular partners available for regulation.