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The Hoatlin team in the middle of solving one of the "most interesting scientific puzzles."

hoatlin123009_1An editorial in the journal Nature Genetics called the study of Fanconi anemia a "tough and simultaneously scientifically rewarding problem." Maureen Hoatlin, Ph.D., Associate Professor, Department of Biochemistry and Molecular Medicine, agrees wholeheartedly. "Our lab is in the middle of solving one of the most interesting scientific puzzles I have ever heard of," said Hoatlin.

Fanconi anemia is a rare genetic disease in children causing short stature, skeletal anomalies, increased susceptibility to solid tumors and leukemia, and bone marrow failure. Although the disease is rare, within a core group of basic scientists worldwide, it is well known because it offers a doorway into unraveling the "caretaker" functions of certain genes over DNA replication and repair. Mutations in these caretaker genes result in the genomic instability and cancer predisposition of Fanconi anemia children.

A major shift in Fanconi anemia research occurred recently with the realization that the Fanconi pathway is enmeshed in the DNA damage response network involving breast cancer susceptibility products BRCA1 and BRCA2.

"Our long-term goal is to obtain a mechanistic explanation for the function of the proteins in the Fanconi anemia 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," said Hoatlin.

Hoatlin's lab has contributed – independently and in collaboration with other research labs worldwide – to an accumulation of knowledge over the last decade that may now be reaching a tipping point. Hoatlin's team developed a novel method to study Fanconi anemia that has accelerated the research trajectory.

In human cells, most of the Fanconi proteins are hard to detect, requiring that investigators grow millions of cells over long periods to collect an adequate sample size. Not only is this costly and time-consuming, the process is not ideal because most of these human cells are not rapidly dividing which is the time when Fanconi proteins are usually at their highest expression.

The Hoatlin team devised a method that chemically triggers DNA copying in extracts from frog's eggs (Xenopus laevis) to activate (in isolation) the Fanconi pathway, monitored by the presence of Fanconi associated proteins. With this technique the team was able to show how the Fanconi proteins function to repair DNA, specifically by preventing the accumulation of breaks in DNA strands that arise even during normal replication.

Based on this insight, the next step, now underway, is to identify chemical compounds that can modulate the Fanconi anemia pathway using the cell-free assay. This offers the potential, for instance, of activating (or bypassing) the pathway in children with the disease. Conversely, compounds that inhibit the Fanconi pathway may be used to reduce human susceptibility to cancer or to enhance the efficiency of anticancer drugs by overriding production of drug-resistance cancer cells.

"There is a great opportunity to create a strong cross-departmental research focus on DNA damage and repair at OHSU with the many complementary research programs we have on the campus," Hoatlin said.

One venue for enhancing the interaction among interested faculty, students and postdocs is the monthly DNA R3 Club that Hoatlin has been running since the summer 2005 (for information Google Hoatlin R3).

"With the excitement about the new collaborations within the Knight Cancer Institute, this is a good time to focus on our combined strengths and interests," Hoatlin said.

Pictured in the photo above from left to right are: Igor Landais (Research Assistant Professor), Sanne Hiddingh (Intern from the University of Applied Sciences in Utrecht, the Netherlands), Chelsea Jenkins (lab assistant), Dr. Maureen Hoatlin, Mimi Muluneh (Intern from the Portland Community College Biosciences Program) and Hemi Ryu (Summer Intern, Johns Hopkins University)


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