|Jason Gorman awarded the 2011 Harold M. Weintraub Graduate Student Award
a graduate student in the Department of Biological Sciences, has been selected for
the 2011 Harold M. Weintraub Graduate Student Award from the Fred Hutchison
Cancer Center in Seattle, WA. This award recognizes outstanding
achievement during graduate studies in the biological sciences.
As an awardee, Jason has been invited to participate in a scientific symposium honoring Hal Weintraub
and his commitment to innovative science. The award symposium will take
place May 6, 2011, at Hutchinson Center's Robert W. Day Campus.
The award is given in honor of Hal Weintraub, a pioneering developmental molecular biologist who died of brain cancer in 1995 at the age of 49; it is one of the most prestigious graduate student awards in the United States.
The recipients for 2011.
Jason Gorman's research
mismatch repair (MMR) corrects mispaired bases that escape
polymerase-proofreading machinery during DNA synthesis before the errors become
permanently embedded in the genome. Disruption of MMR leads to a dramatic
increase in spontaneous point mutations and a predisposition to cancer. In eukaryotes, the protein complexes Msh2-Msh6 and Mlh1-Pms1 are responsible for finding mispaired bases and
To better understand
the mechanisms of MMR Jason developed novel single molecule optical microscopy
assays for directly visualizing fluorescent molecules of Msh2-Msh6 and
Mlh1-Pms1 as they interacted with individual molecules of DNA in real time. Using this approach, Jason demonstrated that both Msh2-Msh6 and Mlh1-Pms1 can diffuse in one-dimension
along DNA. However, they move using two distinct mechanisms: Msh2-Msh6 slowly
slides on DNA while tracking the phosphate backbone, whereas Mlh1-Pms1 hops rapidly
back and forth along DNA. Jason has also shown that Mlh1-Pms1 can hop over
nucleosomes and diffuse along chromatin, whereas Msh2-Msh6 cannot. This work represents the first experimental demonstration that specific
modes of diffusion (i.e. sliding vs.
hopping) impose constraints on protein movement within the context of chromatin,
and these results have important implications for understanding how the
intranuclear trafficking of DNA-binding proteins (e.g. transcription factors, DNA repair proteins, etc.) may be
governed by facilitated diffusion.
Finally, Jason has
developed a novel method for inserting mispaired bases (or any type of DNA
lesion) into a defined position on a 50-kilobase DNA substrate for use in
single molecule imaging assays. Jason's newest work shows
how Msh2-Msh6 binds mispaired bases, how it then recruits Mlh1-Pms1 to the
lesion, and how the two proteins act together to help coordinate downstream
steps in the repair pathway. These
experiments represent a major step forward for the entire field, and will
provide the most comprehensive picture of how MMR proteins identify and respond
to lesions that would otherwise lead to permanent genetic mutations.
Gorman, J. et al.,2007. Molecular Cell 28: 359-370. (Featured
in News & Views, Nature Structural & Molecular Biology Vol. 12, pp. 1124-1125; Rated "Exceptional" by the
Faculty of 1000 Biology: http://f1000biology.com/article/id/1095954/evaluation)
Gorman, J. & Greene, E.C. 2008. Nature Structural
& Molecular Biology 15: 768-74.
Gorman, J. et al., 2010. Nature Structural &
Molecular Biology 17: 932-938. (Recommended
by the Faculty of 1000 Biology: http://f1000biology.com/article/id/4775956/evaluation)