Contact us: email yeast.genetics(at)gmail.com
Kerscher Lab in the news:
How do cells destroy unwanted or harmful proteins? NSF-funded research in the Kerscher lab is deciphering the role that the crosstalk of two small protein modifiers, called SUMO and ubiquitin, plays in this process. One key to understanding this activity are SUMO-targeted ubiquitin ligases (STUbLs), enzymes that can recognize and ubiquitylate SUMO-modified proteins and may signal their destruction by the proteasome. STUbLs are conserved from yeast to humans and play critical roles in chromatin and genome stability. However, STUbL targets and functional roles in SUMO homeostasis are still unclear.
Recently published, NSF-funded research from the Kerscher lab now shows that Siz1, a conserved SUMO ligase that sumoylates a variety of proteins, is amongst the STUbL targets. This is the first example showing that cells may use specialized ubiquitin ligases (STUbLs) to regulate SUMO ligases and hence the level of many sumoylated proteins all at once. The paper from the Kerscher lab describing these novel findings was published in the journal Molecular Biology of the Cell and also features three William & Mary undergraduate co-authors (Eva Syzmanski, Brooke Matson, and Cecilia Esteban), two Biology Masters students (Jason Westerbeck and Mark Guillotte), and a postdoctoral fellow (Nagesh Pasupala): http://www.molbiolcell.org/content/25/1/1.full.pdf. Notably, this project also provides research opportunities for a diverse group of students from Menchville high school, (Newport News, VA) who are helping to clone and purify putative STUbL substrate proteins during a summer internship.
2016: Involving W&M undergraduates in research: Check out this nice coverage of our Tick project collaboration (Drs. Kerscher/Leu/Kaup) at William & Mary:
2012: W&M Raft Debate: Kerscher defends the Natural Sciences
The Flat Hat journal featured an article on Kerscher's defense of the Natural Sciences at the 2012 W&M raft debate -- it was a fun event with 600 students in attendance. Although a close race, the humanities got to take home the raft -- probably because "natural sciences don't dance" :) (photos credit S. Salpukas)
From the research bench:
Biological Research in the ISC: Cure Cancer by Studying Yeast? Yes.
The W&M Ideation magazine featured an article on our lab. For students who are interested in the lab this is a good place to start. You can find the article here:
Working with Budding Yeast:
For most of our research we use budding yeast as a model organism. Much of our research is done using standard pipettes and other research tools ... but we also have enlisted some high-tech help:
Above: Watch our Colony Picking Robot in action (VIDEO above): This is a Norgren Systems CP 7200 colony picking robot in action. The Source plate is in the back and the destination plate in front. The "robot's" needles pick up individual colonies and transfer 384 per plate to the destination plate. Each tungsten needle is then washed and sterilized (orange glowing heater) before rotating along the carrousel to pick up the next colony. In this way we can test arrays of colonies on e.g. media plates with bioactive compounds. There are 20 needles and the robot picks about 4000 colonies on a good afternoon. (C) Kerscher Lab 2008
Research in the Integrated Science Center (ISC):
Above: In 2008 the Kerscher Lab moved to the Integrated Science Center located at the heart of the W&M campus -- the labs are state-of-the-art, and provide ample research and desk-space for students! Above is a picture of lab. You are looking at the main room with 3 rows of bench space. Rooms for the microscope, incubators, and chemicals/media prep are on the right side.
Images of SUMO and Ubiquitin at work:
The Role of SUMO in Chromosome Segregation and Genome Integrity
The Paramount Importance of a Tightly Controlled Chromosome Cycle:
The chromosome cycle defines the controlled duplication, packaging and faithful segregation of an organism’s genetic material from one cell to the next. In humans, the consequences of faulty chromosome segregation and the inability to repair DNA damage have been implicated in cancer, aging and congenital birth defects. Many proteins that can affect the chromosome cycle have been identified and studied using budding yeast, a eukaryotic model organism (see figure) . These yeast proteins often have orthologs in multicellular eukaryotes including humans. My research involves the study of proteins that ensure an efficient chromosome cycle (Ref. 5,6,7), and I focus on the role that a small protein modifier, SUMO, plays in chromosome segregation and genome integrity (Ref. 1,2,3,4). My research plan is particularly well suited for undergraduate research because it combines the tangible and easily mastered budding yeast model organism with a relevant and exciting biological question:
How do Targets and Components of the Sumoylation Machinery Affect the Chromosome Cycle? SUMO, a ubiquitin-like protein, can become covalently attached to specific protein targets. Unlike Ubiquitin, SUMO attachment does not target proteins for degradation, but appears to modulate functional properties like localization, activation, interactions and half-life (2,3). Among the targets of SUMO attachment are proteins that play important roles in the chromosome cycle including the topisomerase Top1 and the DNA helicase Srs2. Regulation of SUMO modification on these proteins is mediated by SUMO ligases and proteases. SUMO ligases, three of which have been identified in yeast to date, ascertain that the right targets are modified with SUMO during the process of SUMO modification. SUMO proteases of the Ulp1 family clip SUMO off the target proteins. Studies with conditional mutants of SUMO and the SUMO protease Ulp1 (see figure below) indicate that SUMO addition and removal is important for mitosis. A temperature sensitive ulp1 mutant (ulp1ts -- Li S.J., Hochstrasser M. (1999)) accumulates high levels of sumoylated proteins, DNA repair intermediates and arrests in mitosis. My work focuses on proteins that interact with Ulp1 in order to understand how SUMO dynamics affect the cell division cycle.
We have recently identified a novel interactor with Ulp1, Slx5. Slx5 is part of a complex with Slx8 and both proteins are involved in genome integrity and the DNA damage response (Ref. 1,2). Together, the Slx5/Slx8 complex constitutes a SUMO-targeted Ubiquitin ligase (STUbL) and ubiquitinates purified Rad52, a protein involved in recombination and DNA repair. Our lab is actively looking for (and testing) additional Slx5/Slx8 substrates. Additionally, we also study a human STUbL protein, RNF4, that can take over the function of Slx5/Slx8 in yeast cells. Since Slx5/Slx8 are involved in genome maintenance we hypothesize that RNF4 plays similar function in human cells.
Figure: YEAST CELLS & NUCLEI: The Ulp1 SUMO protease localizes to the nuclear periphery of yeast cells. Shown are two yeast cells expressing the GFP tagged Ulp1 protein. The image on the left was taken using a fluorescent microscope. An inverted image delineating the cell and nuclear outline is shown on the right. Cell diameter is about 5µm.
1) Ohkuni K, Takahashi Y, Fulp A, Lawrimore J, Au WC, Pasupala N, Levy-Myers R, Warren J, Strunnikov A, Baker RE, Kerscher O.,Bloom K, Basrai MA.(2016) SUMO-Targeted Ubiquitin Ligase (STUbL) Slx5 regulates proteolysis of centromeric histone H3 variant Cse4 and prevents its mislocalization to euchromatin. Mol Biol Cell. 2016 Mar 9. pii: mbc.E15-12-0827.[Epub ahead of print]
8) Cook, E. C, Hochstrasser, M., Kerscher, O. (2009) The SUMO-targeted ubiquitin ligase subunit Slx5 resides in nuclear foci and at sites of DNA breaks Cell Cycle. 8(7): 1080–1089.
9) Yang Xie* , Oliver Kerscher* , Mary B. Kroetz , Heather F. McConchie , Patrick Sung , Mark Hochstrasser. (2007) The yeast HEX3-SLX8 heterodimer is a ubiquitin ligase stimulated by substrate sumoylation. J. Biol Chem. 23(47)34176-34184* denotes joint first authors
10) Kerscher O. (2007) SUMO junction-what's your function? New insights through SUMO-interacting motifs. EMBO Reports 8(6): 550-555
11) Kerscher, O., Felberbaum, R. and Hochstrasser, M. (2006) Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol, 22, 159-180.
12) Kerscher, O., Crotti L.B. & Basrai, M.A. Recognizing Chromosomes in Trouble: Association of the Spindle Checkpoint Protein Bub3p with Altered Kinetochores and a Unique Defective Centromere. Mol. Cell Biol. 23:6406-6418 (2003)
13) Iouk, T.*, Kerscher, O.*, Scott, R. J., Basrai, M. A. & Wozniak, R. W. The yeast nuclear pore complex
functionally interacts with components of the spindle assembly checkpoint. J. Cell Biol. 159:807-819
(2002) * denotes joint first authors
14) Kerscher, O., Hieter, P., Winey, M. & Basrai, M.A. Novel role for a Saccharomyces cerevisiae
nucleoporin, NUP170, in chromosome segregation. Genetics. 157:1543-1553 (2001)
Education & Positions (OK):
• Associate Professor, Biology, The College of William & Mary, Williamsburg, VA, 2012 - present
• Assistant Professor, Biology, The College of William & Mary, Williamsburg, VA, 2006-2012
• Postdoctoral Staff Associate, Hochstrasser Lab, Yale University, New Haven, CT, 2003-2006
• CRTA Fellow, Basrai Lab, The National Cancer Institute, Bethesda, MD, 1999-2003
• Ph.D., Jensen Lab, The Johns Hopkins School of Medicine, BCMB program, Baltimore, MD, 1999
• M.A. in Biotechnology, The Johns Hopkins University, Baltimore, MD, 1995
• B.A. in Biology, The Johns Hopkins University, Baltimore, MD, 1992
• University of Cologne, Biology, Germany, 1987-1988
Work in our lab is supported by NSF grant 1051970 to OK, and the William & Mary Howard Hughes Undergraduate Research Program. Click here for prior funding.