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P. Todd Stukenberg

P. Todd Stukenberg

Professor, Biochemistry and Molecular Genetics

Primary Location
PO Box 800733
1340 JPA Pinn Hall Room 6014A
Charlottesville, VA 22908
Primary Phone Number
434.924.5252
Fax Number
434.924.5069
Email
[email protected]
Website
https://toddstuke.wixsite.com/stukelab

Bio & Overview

Defects in chromosome segregation can generate aneuploidy, a condition that is found in almost all human tumors and is the major cause of miscarriages and birth defects. The complex process of chromosome segregation must be highly regulated to ensure fidelity and prevent aneuploidy. In fact, in a large percentage of tumors the fidelity of mitosis is decreased which can drive tumor progression. Many of the events of mitosis are regulated by the kinetochores and the inner centromere. Kinetochore are assembled on centromeric DNA that bind microtubules and move chromosomes on the mitotic spindle. They also generate the spindle checkpoint signal the ensures that all of the kinetochores are bound to microtubules before they undergo anaphase segregation of chromatids. Inner centromeres are the chromosome region between kinetochores. They are the major site of cohesion between sister chromatids and also contain regulators of kinetochores. This cohesion must be maintained through metaphase and its dissolution is the critical event that triggers anaphase. How kinetochores and inner centromeres coordinate the events of mitosis underlie a number of critical unanswered questions with direct relevance to cancer biology. The Stukenberg lab studies the pathways that 1) power the movements of chromosome movement using the energy stored in the microtubule polymer 2) ensure that the microtubules bound to kinetochores emanate from the correct poles to properly segregate the two sister chromatids in anaphase 3) connect the attachments of microtubules to kinetochores with the generation of the spindle checkpoint signal 4) regulate the transcription from inner centromeres on mitotic chromosomes 5) lower the fidelity of segregation in tumors. Much of our work has focused on the Aurora B kinase which is a critical mitotic regulator that localizes to the inner centromere region from prophase to anaphase. Aurora kinases have become important drug targets for chemotherapeutics. We discovered that Aurora B regulates microtubule dynamics, microtubule attachments to kinetochores and the spindle checkpoint. We are dissecting how Aurora B is regulated and identifying the important substrates that are regulated by Aurora B for proper mitotic progression. The lab performed some of the initial characterization and identified the subunits of the Ndc80 complex, which is the key microtubule attachment point of kinetochores to microtubules. We demonstrated that the Ndc80 complex is required for proper kinetochore assembly, movements of chromosomes and generating the spindle checkpoint signals. We are studying the biophysics and cell biology of Ndc80 to understand how kinetochores move chromosomes and how the spindle checkpoint is coupled to microtubule attachments. We also study how tumors missegregate chromosomes at a higher rate than non-transformed cells, which is known as “Chromosomal Instability”. We utilize bioinformatic approaches to dissect the changes in human tumors that cause the events and recapitulate those changes in model systems.

Academic Information

Department
Biochemistry and Molecular Genetics
Academic Title
Professor

Primary Education

  • BA, Molecular Biology, Colgate University, 1986
  • PhD, Biochemistry, Sloan-Kettering Cancer Institute, and Cornell Medical School, NY, NY., 1993
  • Postdoc, Cell Biology, Harvard Medical Schoolnull

Other Appointments

  • Molecular Physiology and Biological Physics
  • Professor, Cell Biology
  • Professor, MII
  • Professor, BMBG
  • Professor, MCDB

Other Affiliations

  • Program Co-director, GEN Program, Cancer Center
  • Member, Molecular Genetics and Epigenetics Program
  • MSTP
  • Professor, BIMS

Research Interests

Mechanisms of chromosome segregation in Mitosis and generation of Chromosomal Instability in tumors

Research Disciplines

  • Biochemistry
  • Biophysics
  • Cancer Biology
  • Cell and Developmental Biology
  • Epigenetics
  • Genetics
  • Molecular Biology
  • Translational Science

Research Opportunities

  • Biochemistry
  • Bioinformatics & Genomics
  • Cancer Biology
  • Cell Biology
  • Epigenetics
  • Genetics
  • Molecular Biology

PhD Programs

  • Biochemistry & Molecular Genetics
  • Biophysics
  • Cell Biology

Selected Publications

2024

Bryan, N. W., Ali, A., Niedzialkowska, E., Mayne, L., Stukenberg, P. T., & Black, B. E. (2024). Structural basis for the phase separation of the chromosome passenger complex. ELIFE, 13. doi:10.7554/eLife.92709

Niedzialkowska, E., Truong, T. M., Eldredge, L. A., Ali, A., Redemann, S., & Stukenberg, P. T. (2024). Chromosomal passenger complex condensates generate parallel microtubule bundles in vitro.. The Journal of biological chemistry, 300(3), 105669. doi:10.1016/j.jbc.2024.105669

2023

Ali, A., & Stukenberg, P. T. (2023). Aurora kinases: Generators of spatial control during mitosis. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 11. doi:10.3389/fcell.2023.1139367

2022

Janczyk, P. L., Zylkiewicz, E., De Hoyos, H., West, T., Matson, D. R., Choi, W. -C., . . . Stukenberg, P. T. (2023). Aurora A phosphorylates Ndel1 to reduce the levels of Mad1 and NuMA at spindle poles. MOLECULAR BIOLOGY OF THE CELL, 34(1). doi:10.1091/mbc.E21-09-0438

Morris, B. B., Smith, J. P., Zhang, Q., Jiang, Z., Hampton, O. A., Churchman, M. L., . . . Mayo, M. W. (2022). Replicative Instability Drives Cancer Progression. BIOMOLECULES, 12(11). doi:10.3390/biom12111570

Niedzialkowska, E., Liu, L., Kuscu, C., Mayo, Z., Minor, W., Strahl, B. D., . . . Stukenberg, P. T. (2022). Tip60 acetylation of histone H3K4 temporally controls chromosome passenger complex localization.. Molecular biology of the cell, 33(9), br15. doi:10.1091/mbc.e21-06-0283

2021

Matson, D. R., Denu, R. A., Zasadil, L. M., Burkard, M. E., Weaver, B. A., Flynn, C., & Stukenberg, P. T. (2021). High nuclear TPX2 expression correlates with TP53 mutation and poor clinical behavior in a large breast cancer cohort, but is not an independent predictor of chromosomal instability. BMC CANCER, 21(1). doi:10.1186/s12885-021-07893-7

2020

Trivedi, P., & Stukenberg, P. T. (2020). A Condensed View of the Chromosome Passenger Complex. TRENDS IN CELL BIOLOGY, 30(9), 676-687. doi:10.1016/j.tcb.2020.06.005

Morris, B. B., Wages, N. A., Grant, P. A., Stukenberg, P. T., Gentzler, R. D., Hall, R. D., . . . Mayo, M. W. (2021). MYBL2-Driven Transcriptional Programs Link Replication Stress and Error-prone DNA Repair With Genomic Instability in Lung Adenocarcinoma. FRONTIERS IN ONCOLOGY, 10. doi:10.3389/fonc.2020.585551

2019

Trivedi, P., Palomba, F., Niedzialkowska, E., Digman, M. A., Gratton, E., & Stukenberg, P. T. (2019). The inner centromere is a biomolecular condensate scaffolded by the chromosomal passenger complex. NATURE CELL BIOLOGY, 21(9), 1127-+. doi:10.1038/s41556-019-0376-4

Trivedi, P., Zaytsev, A. V., Godzi, M., Ataullakhanov, F. I., Grishchuk, E. L., & Stukenberg, P. T. (2019). The binding of Borealin to microtubules underlies a tension independent kinetochore-microtubule error correction pathway. NATURE COMMUNICATIONS, 10. doi:10.1038/s41467-019-08418-4

2018

Szlachta, K., Kuscu, C., Tufan, T., Adair, S. J., Shang, S., Michaels, A. D., . . . Adli, M. (2018). CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response. NATURE COMMUNICATIONS, 9. doi:10.1038/s41467-018-06676-2

Pfister, K., Pipka, J. L., Chiang, C., Liu, Y., Clark, R. A., Keller, R., . . . Stukenberg, P. T. (2018). Identification of Drivers of Aneuploidy in Breast Tumors. CELL REPORTS, 23(9), 2758-2769. doi:10.1016/j.celrep.2018.04.102

Manukyan, A., Sargsyan, L., Parsons, S. J., & Stukenberg, P. T. (2018). P190RhoGAP prevents mitotic spindle fragmentation and is required to activate Aurora A kinase at acentriolar poles. CHROMOSOMA, 127(3), 375-386. doi:10.1007/s00412-018-0670-0

2017

Janczyk, P. L., Skorupka, K. A., Tooley, J. G., Matson, D. R., Kestner, C. A., West, T., . . . Stukenberg, P. T. (2017). Mechanism of Ska Recruitment by Ndc80 Complexes to Kinetochores. DEVELOPMENTAL CELL, 41(4), 438-+. doi:10.1016/j.devcel.2017.04.020

2016

Barnhart-Dailey, M. C., Trivedi, P., Stukenberg, P. T., & Foltz, D. R. (2017). HJURP interaction with the condensin II complex during G1 promotes CENP-A deposition. MOLECULAR BIOLOGY OF THE CELL, 28(1), 54-64. doi:10.1091/mbc.E15-12-0843

Sivakumar, S., Janczyk, P. L., Qu, Q., Brautigam, C. A., Stukenberg, P. T., Yu, H., & Gorbsky, G. J. (2016). The human SKA complex drives the metaphase-anaphase cell cycle transition by recruiting protein phosphatase 1 to kinetochores. ELIFE, 5. doi:10.7554/eLife.12902

2015

Trivedi, P., & Stukenberg, P. T. (2016). A Centromere-Signaling Network Underlies the Coordination among Mitotic Events. TRENDS IN BIOCHEMICAL SCIENCES, 41(2), 160-174. doi:10.1016/j.tibs.2015.11.002

Grant, I. M., Balcha, D., Hao, T., Shen, Y., Trivedi, P., Patrushev, I., . . . Gilchrist, M. J. (2015). The Xenopus ORFeome: A resource that enables functional genomics. DEVELOPMENTAL BIOLOGY, 408(2), 345-357. doi:10.1016/j.ydbio.2015.09.004

Stukenberg, P. T., & Burke, D. J. (2015). Connecting the microtubule attachment status of each kinetochore to cell cycle arrest through the spindle assembly checkpoint. CHROMOSOMA, 124(4), 463-480. doi:10.1007/s00412-015-0515-z

Eagleson, G., Pfister, K., Knowlton, A. L., Skoglund, P., Keller, R., & Stukenberg, P. T. (2015). Kif2a depletion generates chromosome segregation and pole coalescence defects in animal caps and inhibits gastrulation of the Xenopus embryo. MOLECULAR BIOLOGY OF THE CELL, 26(5), 924-937. doi:10.1091/mbc.E13-12-0721

Krizaic, I., Williams, S. J., Sanchez, P., Rodriguez-Corsino, M., Stukenberg, P. T., & Losada, A. (2015). The distinct functions of CENP-C and CENP-T/W in centromere propagation and function in Xenopus egg extracts. NUCLEUS, 6(2), 133-143. doi:10.1080/19491034.2014.1003509

2014

Manukyan, A., Ludwig, K., Sanchez-Manchinelly, S., Parsons, S. J., & Stukenberg, P. T. (2015). A complex of p190RhoGAP-A and anillin modulates RhoA-GTP and the cytokinetic furrow in human cells. JOURNAL OF CELL SCIENCE, 128(1), 50-60. doi:10.1242/jcs.151647

Matson, D. R., & Stukenberg, P. T. (2014). CENP-I and Aurora B act as a molecular switch that ties RZZ/Mad1 recruitment to kinetochore attachment status.. The Journal of cell biology, 205(4), 541-554. doi:10.1083/jcb.201307137

Banerjee, B., Kestner, C. A., & Stukenberg, P. T. (2014). EB1 enables spindle microtubules to regulate centromeric recruitment of Aurora B. JOURNAL OF CELL BIOLOGY, 204(6), 947-963. doi:10.1083/jcb.201307119

Matson, D. R., & Stukenberg, P. T. (2014). CENP-I and Aurora B act as a molecular switch that ties RZZ/Mad1 recruitment to kinetochore attachment status. JOURNAL OF CELL BIOLOGY, 205(4), 541-554. doi:10.1083/jcb.201307137

Zylkiewicz, E., & Stukenberg, P. T. (2014). Xenopus Egg Extracts as a Simplified Model System for Structure-Function Studies of Dynein Regulators. MITOSIS: METHODS AND PROTOCOLS, 1136, 117-133. doi:10.1007/978-1-4939-0329-0_8

2013

Earnshaw, W. C., Allshire, R. C., Black, B. E., Bloom, K., Brinkley, B. R., Brown, W., . . . Cleveland, D. W. (2013). Esperanto for histones: CENP-A, not CenH3, is the centromeric histone H3 variant. CHROMOSOME RESEARCH, 21(2), 101-106. doi:10.1007/s10577-013-9347-y

2012

Alushin, G. M., Musinipally, V., Matson, D., Tooley, J., Stukenberg, P. T., & Nogales, E. (2012). Multimodal microtubule binding by the Ndc80 kinetochore complex. NATURE STRUCTURAL & MOLECULAR BIOLOGY, 19(11), 1161-+. doi:10.1038/nsmb.2411

Utepbergenov, D., Derewenda, U., Olekhnovich, N., Szukalska, G., Banerjee, B., Hilinski, M. K., . . . Derewenda, Z. S. (2012). Insights into the Inhibition of the p90 Ribosomal 56 Kinase (RSK) by the Flavonol Glycoside SL0101 from the 1.5 Å Crystal Structure of the N-Terminal Domain of RSK2 with Bound Inhibitor. BIOCHEMISTRY, 51(33), 6499-6510. doi:10.1021/bi300620c

Matson, D. R., & Stukenberg, P. T. (2012). Cdt1 throws kinetochore-microtubule attachments for a loop. NATURE CELL BIOLOGY, 14(6), 561-563. doi:10.1038/ncb2513

Matson, D. R., Demirel, P. B., Stukenberg, P. T., & Burke, D. J. (2012). A conserved role for COMA/CENP-H/I/N kinetochore proteins in the spindle checkpoint. GENES & DEVELOPMENT, 26(6), 542-547. doi:10.1101/gad.184184.111

Niedzialkowska, E., Wang, F., Porebski, P. J., Minor, W., Higgins, J. M. G., & Stukenberg, P. T. (2012). Molecular basis for phosphospecific recognition of histone H3 tails by Survivin paralogues at inner centromeres. MOLECULAR BIOLOGY OF THE CELL, 23(8), 1457-1466. doi:10.1091/mbc.E11-11-0904

Foltz, D. R., & Stukenberg, P. T. (2012). A New Histone at the Centromere?. CELL, 148(3), 394-396. doi:10.1016/j.cell.2012.01.023

2011

Beum, P. V., Lindorfer, M. A., Peek, E. M., Stukenberg, P. T., de Weers, M., Beurskens, F. J., . . . Taylor, R. P. (2011). Penetration of antibody-opsonized cells by the membrane attack complex of complement promotes Ca2+ influx and induces streamers. EUROPEAN JOURNAL OF IMMUNOLOGY, 41(8), 2436-2446. doi:10.1002/eji.201041204

Alexander, J., Lim, D., Joughin, B. A., Hegemann, B., Hutchins, J. R. A., Ehrenberger, T., . . . Yaffe, M. B. (2011). Spatial Exclusivity Combined with Positive and Negative Selection of Phosphorylation Motifs Is the Basis for Context-Dependent Mitotic Signaling. SCIENCE SIGNALING, 4(179). doi:10.1126/scisignal.2001796

Zheng, M., Cierpicki, T., Burdette, A. J., Utepbergenov, D., Janczyk, P. L., Derewenda, U., . . . Derewenda, Z. S. (2011). Structural Features and Chaperone Activity of the NudC Protein Family. JOURNAL OF MOLECULAR BIOLOGY, 409(5), 722-741. doi:10.1016/j.jmb.2011.04.018

Matson, D. R., & Stukenberg, P. T. (2011). Spindle Poisons and Cell Fate: A Tale of Two Pathways. MOLECULAR INTERVENTIONS, 11(2), 141-150. doi:10.1124/mi.11.2.12

Tooley, J. G., Miller, S. A., & Stukenberg, P. T. (2011). The Ndc80 complex uses a tripartite attachment point to couple microtubule depolymerization to chromosome movement. MOLECULAR BIOLOGY OF THE CELL, 22(8), 1217-1226. doi:10.1091/mbc.E10-07-0626

Tooley, J., & Stukenberg, P. T. (2011). The Ndc80 complex: integrating the kinetochore's many movements. CHROMOSOME RESEARCH, 19(3), 377-391. doi:10.1007/s10577-010-9180-5

Zylkiewicz, E., Kijanska, M., Choi, W. -C., Derewenda, U., Derewenda, Z. S., & Stukenberg, P. T. (2011). The N-terminal coiled-coil of Ndell is a regulated scaffold that recruits LIS1 to dynein. JOURNAL OF CELL BIOLOGY, 192(3), 433-445. doi:10.1083/jcb.201011142

Banerjee, B., & Stukenberg, P. (2011). Regulation of the Chromosomal Passenger Complex. MOLECULAR BIOLOGY OF THE CELL, 22. Retrieved from https://www.webofscience.com/

Matson, D. R., Demeril, P., Burke, D. J., & Stukenberg, P. T. (2011). COMA/CENP-H/I/K kinetochore proteins and Aurora B kinase are required to generate the spindle checkpoint.. MOLECULAR BIOLOGY OF THE CELL, 22. Retrieved from https://www.webofscience.com/

2010

Wang, F., Dai, J., Daum, J. R., Niedzialkowska, E., Banerjee, B., Stukenberg, P. T., . . . Higgins, J. M. G. (2010). Histone H3 Thr-3 Phosphorylation by Haspin Positions Aurora B at Centromeres in Mitosis. SCIENCE, 330(6001), 231-235. doi:10.1126/science.1189435

Stukenberg, P. T., & Foltz, D. R. (2010). Kinetochores: Orchestrating the Chromosomal Minuet. CURRENT BIOLOGY, 20(12), R522-R525. doi:10.1016/j.cub.2010.05.017