Graduate Studies Faculty

Bruce Knutson, PhD

Bruce Knutson, PhD
Appointed 09/02/14
3223A Weiskotten Hall
766 Irving Ave.
Syracuse, NY 13210

315 464-8709

Current Appointments

Hospital Campus

Research Programs and Affiliations

  • Biochemistry and Molecular Biology
  • Biomedical Sciences Program

Research Interests

  • RNA polymerase I transcription (structure, assembly, regulation), nucleolar biology, macromolecular architecture, crosslinking, proteomics, bioinformatics, modeling, molecular genetics, biochemistry, model systems

Research

Fig.1. the nucleolus
Fig.1. The nucleolus

A century old hallmark of cancer is an enlarged nucleolus (Fig.1), a unique nuclear sub compartment where RNA polymerase I (Pol I) transcription and ribosome biogenesis take place. Pol I transcription is unregulated in cancer cells and drives cell proliferation, making it an attractive anti-cancer therapeutic target. The major focus of our research is to elucidate the molecular mechanism of Pol I transcription and how its dysregulation leads to cancer and disease. Our research uses an innovative cross-organismal and interdisciplinary approach that integrates bioinformatics, biochemistry, computational biology, genetics, proteomics and structural biology in yeast and human model system.

Molecular architecture of the Pol I preinitiation complex (PIC)

Fig. 2. Pol I PIC Model
Fig. 2. Pol I PIC Model

Pol I transcription begins with the formation of the PIC (Fig.2), a macromolecular assemblage of more than 20 different proteins that function coordinately to accurately position Pol I at the promoter and to help initiate transcription. We are interested in the key structural facets of Pol I PIC formation and how it's altered in cancer and diseased cells. Our lab uses an integrated combination of sophisticated protein-protein interaction mapping technologies such as combined chemical crosslinking/mass spectrometry to determine the spatial orientation of Pol I PIC components and how they change during the transcription cycle and in diseased states.

Pol I and craniofacial dysmorphology. Mutations in Pol I cause an autosomal dominant craniofacial abnormality called Treacher Collins Syndrome (TCS). TCS is characteried by an underdeveloped lower jaw and cheekbones that is treated by an extensive multi-stage surgical reconstruction from childhood to early adulthood. We are interested in how these Pol I mutations cause TCS, how they affect Pol I activity, and how they can be suppressed to prevent the disease. Currently, there are no known cures for TCS and other related craniofacial dysmorphologies.

Fig.3. Pol I Regulation
Fig.3. Pol I Regulation

Pol I dysregulation in cancer. The upregulation of Pol I transcription in cancer cells coincides with activating mutations in many oncogenes and loss of function mutations in tumor suppressors that are believed to directly regulate Pol I activity (Fig.3). However, their bona fide Pol I targets and sites of interaction remain unclear. To understand how these cancer proteins target the Pol I complex, we use a combination of protein crosslinking technologies coupled of molecular genetics and biochemistry to identify and characterize the direct and functionally relevant in vivo Pol I targets. These studies will illuminate new strategies to control aberrant Pol I activity.

Graduate research in the Knutson Lab. Interested students should directly contact Bruce Knutson to discuss available research opportunities.

Knutson BA, Smith ML, Walker-Kopp N, Xu X. Super elongation complex contains a TFIIF-related subcomplex. Transcription. 2016. 7(4):133-40

Knutson BA, Lui J, Ranish J. Hahn S. Architecture of the S.cerevisiae RNA polymerase I Core Factor complex. Nature Structural and Molecular Biology. 2014. 21(9): 810-816

Knutson BA, Hahn S. TFIIB-related factors in RNA polymerase I transcription. Biochem Biophys Acta. 2013. 1829(3-4): 265-273

Knutson BA. Emergence and expansion of TFIIB-like factors in the plant kingdom. Gene. 2013. 526(1): 30-38

Knutson BA, Hahn S. Yeast Rrn7 and human TAF1B are TFIIB-related RNA polymerase I general transcription factors. Science. 2011. 33(6049): 1637-40

Knutson BA, Hahn S. Domains of Tra1 important for activator recruitment and transcription coactivator functions of SAGA and NuA4 complexes. Mol Cell Biol. 2011. 31(4): 818-831

Knutson BA. Insights into the domain and repeat architecture of target of rapamycin. J Struct Biol. 2010. 170(2): 354-63

Faculty Profile Shortcut: http://www.upstate.edu/faculty/knutsonb
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