Hoatlin:Research Interests

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Molecular Mechanism of Human Cancer Susceptibility

Highly specialized and partially redundant mechanisms have evolved to maintain genomic stability. New evidence suggests that one of these mechanisms is defective in Fanconi anemia (FA), a genetic model for human host susceptibility to cancer. FA is a rare but devastating multi-gene disease thought to have an underlying defect in DNA interstrand crosslink repair. Current models suggest that a trigger point for the FA pathway is the activation of a downstream protein, FANCD2. A set of functionally-interdependent FA “core complex” proteins is indispensable for the function of FANCD2. How the core complex proteins mediate the enigmatic downstream function of FANCD2 is unclear. Emerging evidence links FANCD2 to DNA repair proteins BRCA1 and BRCA2 (also known as FA protein FANCD1), and a role in the DNA damage response during S-phase.

We developed cell-free assays for FA proteins based on replicating extracts from Xenopus eggs to dissect the key functional events during S-phase. These extracts allow us to analyze FA protein function and post-translational modifications during ongoing DNA synthesis that is precisely synchronized and under natural cell cycle control. The regulated association of xFANCD2 and core complex proteins with chromatin in S-phase is providing us with a biochemical platform for elucidating FANCD2 and FA core complex protein molecular function during events in DNA replication and repair.

Our long-term goal is to obtain a mechanistic explanation for the function of the proteins in the FA pathway. We hope our work will lead to new approaches for targeted drug design in Fanconi anemia, as well as for cancer prevention and treatment in the general population.

For more background about the proteins that participate in the Fanconi anemia/BRCA pathway please see Background.

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