NGEC Principal Investigator
Professor of Genome Sciences and Pathology
University of Washington
Department of Biochemistry
University of Washington School of Medicine
Health Sciences K-072C, Box 357705
1959 N.E. Pacific St.
Seattle, WA 98195
Tel: (206) 616-7392 Fax: (206) 543-3967
E-mail Dr. Monnat
Dr. Monnat received his BS in Zoology from the University of Wisconsin and earned his MD from the University of Chicago. He then completed residency training and a postdoctoral fellowship at the University of Washington in Seattle.
Dr. Monnat is the principal investigator for the NGEC in the area of Novel Homing Endonucleases for Genome Engineering.
“The NGEC is a new and exciting opportunity to bring our longstanding interest in homing endonucleases to bear on practical as well as more basic problems in human biology and disease.”As part of its role in the NGEC, the Monnat laboratory is working to:
The Monnat lab has had a very longstanding interest in using homing endonucleases for both fundamental biology and for disease research and therapy. The NGEC is a realization of Dr. Monnat and his team’s original work over the past 15 years to identify and develop homing endonucleases as genomics reagents. The lab seeks to answer questions such as: What new proteins can be found in nature? What new proteins can be engineered from nature’s “starter set”? What are the functional properties of HEG’s as genome engineering reagents in mammalian cells?
Key lab personnel assisting this work include Hui Li (postdoctoral fellow), Stefan Pellenz (postdoctoral fellow) and Umut Ulge (graduate/MD-PhD student).
The Monnat LabThe Monnat laboratory research focuses on molecular mechanisms that insure the faithful transmission of genetic information in human somatic cells, and on the generation of novel genome engineering reagents for biology and medicine. The lab conducts research in two key areas:
Genetic stability mechanisms: The Monnat lab works on a small gene family, the human RecQ helicases, which play key roles in nucleic acid metabolism and genetic stability assurance. Loss of function of three of these proteins, WRN, BLM and RECQ4, are associated with the heritable genetic instability/cancer predisposition diseases Werner, Bloom and Rothmund-Thomson syndromes. Research at the lab is focused on in vivo functions of these proteins, on regulation and on functional redundancy between different members of the human RecQ helicase family.
Genome engineering: Homing endonucleases are highly site-specific endonucleases that catalyze the lateral transfer of parasitic DNA elements in all Kingdoms of life. Dr. Monnat and his team have characterized structures and target site specificities of members of two families of these proteins, and have used results to engineer novel chimeric homing endonucleases with altered target site specificities. These new gene-specific reagents are being used for genome engineering, and have potential for disease therapy and prevention.
Close-up view of the representative homodimer I¬CreI showing the dimer/domain interface alpha helices and three-metal active site characteristic of the LAGLIDADG homing endonuclease family.
Ashworth, J., Havranek, J.J., Duarte, C.M., Sussman, D., Monnat, R.J., Jr., Stoddard, B.L. and Baker, D. (2006) Computational redesign of endonuclease DNA binding and cleavage specificity. Nature 441:656-659.
Dhillon,K., Sirorova, J., Saintigny,Y., Poot,M., Gollahon,K., Rabinovitch, P.S. and Monnat, R.J.,Jr. (2007) Functional role of the Werner syndrome RecQ helicase in human fibroblasts. Aging Cell 6: 53-61.
Volna, P., Jarjour, J. Baxter, S., Roffler, S., Monnat, RJ Jr., Stoddard, B. and Scharenberg, A. (2007) Flow cytometric analysis of DNA binding and cleavage by cell surface-displayed homing endonucleases. Nucleic Acids Research 35: 2748-2758.
Berkovich, E., Monnat, RJ Jr. and Kastan, M. (2007) Roles of ATM and NBS1 in chromatin structure modulation and DNA double strand break repair. Nature Cell Biology 9: 683-690.
Kudlow, B., Kennedy, B.K., and Monnat, RJ Jr. (2007) Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nature Reviews Molecular and Cellular Biology 8: 394-404.