![布鲁斯·克努森的头像](/site-assets/images/portraits/knutsonb-175w.jpg)
布鲁斯·克努森博士
语言
研究项目和附属机构
研究兴趣
RNA聚合酶I转录(结构, 组装, 监管), 核仁的生物学, 大分子结构, 交联, 蛋白质组学, 生物信息学, 建模, 分子遗传学, 生物化学, 模型系统
研究抽象
![无花果.1. 核仁的](http://zb1.jinken-fukuoka.com/scripts/faculty/abstract/images/knutsonb-1.jpg)
A century old hallmark of cancer is an enlarged nucleolus (图.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 生物信息学, 生物化学, 计算生物学, 遗传学, 蛋白质组学 and structural biology in yeast and human model system.
Molecular architecture of the Pol I preinitiation complex (PIC)
![无花果. 2. Pol I PIC模型](http://zb1.jinken-fukuoka.com/scripts/faculty/abstract/images/knutsonb-2.jpg)
Pol I transcription begins with the formation of the PIC (图.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 交联/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与颅面畸形. 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, 它们如何影响Pol I活性, and how they can be suppressed to prevent the disease. Currently, there are no known cures for TCS and other related craniofacial dysmorphologies.
![无花果.3. Pol规例](http://zb1.jinken-fukuoka.com/scripts/faculty/abstract/images/knutsonb-3.jpg)
Pol I在癌症中的失调. 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 (图.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 交联 technologies coupled of 分子遗传学 and 生物化学 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.
克努森实验室的研究生研究. Interested students should directly contact Bruce Knutson to discuss available research opportunities.
克努森巴, McNamar R, Rothblum LI. Dynamics of the RNA polymerase I TFIIF/TFIIE-like subcomplex: a mini-review. 生物化学Soc. 2020年10月30日;48(5):1917-1927. doi: 10.1042 / BST20190848.
克努森巴, Smith ML, Belkevich AE, Fakhouri AM. Molecular 前ology of RNA Polymerase I Upstream Activation Factor. Mol细胞生物学. 2020年6月15日;40(13):e00056-20. doi: 10.1128 / MCB.00056-20. 2020年6月15日.
McNamar R, Abu-Adas Z, Rothblum K, 克努森巴, Rothblum LI. Conditional depletion of the RNA polymerase I subunit PAF53 reveals that it is essential for mitosis and enables identification of functional domains. 生物化学. 2019年12月27日;294(52):19907-19922. doi: 10.1074 / jbc.RA119.009902. Epub 2019 11月
Jackobel AJ, Zeberl BJ, Glover DM, Fakhouri AM, 克努森巴. S. cerevisiae RNA polymerase I Core Factor reveal a preference for the GC-minor groove and a conserved binding mechanism. 生物化学,生物物理,基因调控机制. 2019年9月,1862 (9):194408. doi: 10.1016/j.bbagrm.2019.194408. Epub 2019 8月2日.
Smith ML, Cui W, Jackobel AJ, Walker-Kopp N, Knutson. Reconstitution of RNA Polymerase I Upstream Activating Factor and the Roles of Histones H3 and H4 in Complex Assembly. J摩尔生物学. 2018年Epub
韩勇,何勇,刘建军,刘建军. Breaking the mold: structures of the RNA polymerase I transcription complex reveal a new path for initiation. 转录. 2018年1月15:1-7
Walker-Kopp N, Jackobel AJ, Pannafino GN, Morocho PA, Xu X, 克努森巴. Treacher Collins syndrome mutations in Saccharomyces cerevisiae destabilize RNA polymerase I and III complex integrity. Hum Mol 基因t. 2017年11月1日;26(21):4290-4300.
Han Y, Yan C, Nguyen THD, Jackobel AJ, Ivanov I, 克努森巴, He Y. Structural mechanism of ATP-independent transcription initiation by RNA polymerase I. Elife. 5 . 2017年6月17日.
克努森巴, Smith ML, Walker-Kopp N, Xu X. Super elongation complex contains a TFIIF-related subcomplex. 转录. 2016. 7(4):133-40
克努森巴, Lui J, Ranish J. 哈恩年代. S的体系结构.cerevisiae RNA polymerase I Core Factor complex. 自然、结构与分子生物学. 2014. 21(9): 810-816
克努森巴, 哈恩年代. TFIIB-related factors in RNA polymerase I transcription. 生物化学学报. 2013. 1829(3-4): 265-273
克努森巴. Emergence and expansion of TFIIB-like factors in the plant kingdom. 基因. 2013. 526(1): 30-38
克努森巴, 哈恩年代. Yeast Rrn7 and human TAF1B are TFIIB-related RNA polymerase I general transcription factors. 科学. 2011. 33(6049): 1637-40
克努森巴, 哈恩年代. Domains of Tra1 important for activator recruitment and transcription coactivator functions of SAGA and NuA4 complexes. Mol细胞生物学. 2011. 31(4): 818-831
克努森巴. Insights into the domain and repeat architecture of target of rapamycin. [J]结构生物学. 2010. 170(2): 354-63