Molecular Genetics I
Molecular Genetics I
Prof. Dr. Stefan Westermann
Faculty of Biology
Center of Medical Biotechnology (ZMB)
University of Duisburg-Essen
Chromosome segregation, Kinetochores and the Microtubule Cytoskeleton
Starting out from a single fertilized egg, an adult human body contains about 100 Trillion cells. All cells in an organism are generated by division of existing cells, and the genomic building plan of the organism, in the form of chromosomes, needs to be exactly copied and divided between cells during the division process. How do cells achieve the segregation of their genomes with such remarkable precision? What type of molecular defects may underlie errors in chromosome segregation, which can give rise to chromosomal aneuploidies, birth defects and cancer?
Our laboratory is striving to understand how the genome is passed accurately from one cell generation to the next. To achieve this goal we are pursuing two closely related research questions:
1. How are Kinetochores constructed to allow accurate chromosome segregation in eukaryotic cells? We are performing a detailed functional analysis and biochemical reconstitution of the budding yeast kinetochore.
2. How are Microtubules organized and regulated to segregate chromosomes? We are investigating how molecular motor proteins, plus-end binders, and other microtubule-associated proteins work together in order to regulate and organize microtubules during cell division.
Experimental Approaches
We take full advantage of the rich repertoire of genetic, biochemical and cell biological tools in the model system Saccharomyces cerevisiae. Our experiments typically integrate biochemical reconstitution in vitro with genetic and cell biological analysis in yeast cells. Specifically we perform:
- In-vitro reconstitution and biochemical analysis of proteins and multi-protein complexes.
- Yeast genetics and functional analysis of the chromosome segregation machinery in vivo.
- Advanced fluorescence imaging techniques, such as total internal reflection fluorescence microscopy and reconstituted assays for dynamic microtubule growth.
Dudziak A, Pleuger R, Schmidt J, Hamm F, Tendulkar S, Janen K, Vetter IR, Singh S, Fischbock J, Herzog F, and Westermann S. (2025).
The Spc105/Kre28 complex promotes mitotic error correction by outer kinetochore recruitment of Ipl1/Sli15.
EMBO J. 10.1038/s44318-025-00437-w.
Pleuger R, Cozma C, Hohoff S, Denkhaus C, Dudziak A, Kaschani F, Kaiser M, Musacchio A, Vetter IR, and Westermann S. (2024).
Microtubule end-on attachment maturation regulates Mps1 association with its kinetochore receptor.
Curr Biol 34, 2279-2293 e2276. 10.1016/j.cub.2024.03.062.
Kornakov N, and Westermann S. (2023).
Systematic analysis of microtubule plus-end networks defines EB-cargo complexes critical for mitosis in budding yeast.
Mol Biol Cell 34, ar37. 10.1091/mbc.E23-02-0054.
Neblik J, Kirupakaran A, Beuck C, Mieres-Perez J, Niemeyer F, Le MH, Telgheder U, Schmuck JF, Dudziak A, Bayer P, et al. (2023).
Multivalent Molecular Tweezers Disrupt the Essential NDC80 Interaction with Microtubules.
J Am Chem Soc 145, 15251-15264. 10.1021/jacs.3c02186.
Dudziak A, Engelhard L, Bourque C, Klink BU, Rombaut P, Kornakov N, Janen K, Herzog F, Gatsogiannis C, and Westermann S. (2021).
Phospho-regulated Bim1/EB1 interactions trigger Dam1c ring assembly at the budding yeast outer kinetochore.
EMBO J 40, e108004. 10.15252/embj.2021108004.
Böhm M, Killinger K, Dudziak A, Pant P, Jänen K, Hohoff S, Mechtler K, Örd M, Loog M, Sanchez-Garcia E, and Westermann S. (2021).
Cdc4 phospho-degrons allow differential regulation of Ame1CENP-U protein stability across the cell cycle.
eLife 10, e67390. 10.7554/eLife.67390.
Kornakov N, Möllers B, and Westermann S. (2020).
The EB1–Kinesin-14 complex is required for efficient metaphase spindle assembly and kinetochore bi-orientation.
Journal of Cell Biology 219. 10.1083/jcb.202003072.
Killinger K, Bohm M, Steinbach P, Hagemann G, Bluggel M, Janen K, Hohoff S, Bayer P, Herzog F, and Westermann S. (2020).
Auto-inhibition of Mif2/CENP-C ensures centromere-dependent kinetochore assembly in budding yeast.
EMBO J 39, e102938. 10.15252/embj.2019102938.
Schmitzberger F, Richter MM, Gordiyenko Y, Robinson CV, Dadlez M, and Westermann S. (2017).
Molecular basis for inner kinetochore configuration through RWD domain-peptide interactions.
EMBO J 36, 3458-3482. 10.15252/embj.201796636.
van der Vaart B, Fischböck J, Mieck C, Pichler P, Mechtler K, Medema RH, and Westermann S. (2017).
TORC1 signaling exerts spatial control over microtubule dynamics by promoting nuclear export of Stu2.
The Journal of Cell Biology 216, 3471-3484. 10.1083/jcb.201606080.
Pekgoz Altunkaya G, Malvezzi F, Demianova Z, Zimniak T, Litos G, Weissmann F, Mechtler K, Herzog F, and Westermann S. (2016).
CCAN Assembly Configures Composite Binding Interfaces to Promote Cross-Linking of Ndc80 Complexes at the Kinetochore.
Curr Biol 26, 2370-2378. 10.1016/j.cub.2016.07.005.
Molodtsov MI, Mieck C, Dobbelaere J, Dammermann A, Westermann S, and Vaziri A. (2016).
A Force-Induced Directional Switch of a Molecular Motor Enables Parallel Microtubule Bundle Formation.
Cell 167, 539-552 e514. 10.1016/j.cell.2016.09.029.
Molecular Stop Signal Identified The Surveillance System of Cell Division
[04.06.2024] Several million cells divide every second in our bodies. During nuclear division (mitosis), the genetic material must be distributed correctly and completely between the daughter cells - errors in this process can lead to defective developments or genetic disorders, and many cancer cells are also characterised by unequal numbers of chromosomes. Therefore, if errors in the division process become apparent, the cell can stop it. Biologists at the University of Duisburg-Essen have been able to elucidate this process at a molecular level. The scientific journal ‘Current Biology’ has published their findings.
The DFG-funded CRC 1430 "Molecular Mechanisms of Cell State Transitions" explores fundamental molecular mechanisms that underlie the regulation of cell proliferation. Cell proliferation needs to be tightly controlled to ensure organismal development and tissue regeneration, while preventing neoplastic disorders. A key hallmark of this control is the establishment of distinct, biochemically or epigenetically defined cell states and the regulated transitions between these states.
Project Area A - Biology and Molecular Oncology
Project A01 - Prof. Dr. Stefan Westermann:
Molecular control of kinetochore-microtubule interactions at the metaphase-anaphase transition