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Stukenberg, P. Todd

P. Todd Stukenberg

Primary Appointment

Biochemistry and Molecular Genetics

Contact Information

PO Box 800733
Charlottesville, VA 22908
Telephone: 434-924-5252
Fax: 434- 924 -5069
Email: pts7h@virginia.edu
Website: https://toddstuke.wixsite.com/stukelab

Research Interests

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

Research Description

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.

Selected Publications

Janczyk Pawel, Skorupa KA, Tooley JG, Matson DR, Kestner CA, West T, Pornillos O, Stukenberg PT, Mechanism of Ska Recruitment by Ndc80 Complexes to Kinetochores., ; Developmetal Cell. 41(4) 438-449 | PMCID: 28535377

Sivakumar S, Janczyk P?, Qu Q, Brautigam CA, Stukenberg PT, Yu H, Gorbsky GJ, The human SKA complex drives the metaphase-anaphase cell cycle transition by recruiting protein phosphatase 1 to kinetochores., 2016; eLife. 5() PMID: 26981768 | PMCID: PMC4821802

Barnhart-Dailey MC, Trivedi P, Stukenberg PT, Foltz DR, HJURP interaction with the condensin II complex during G1 promotes CENP-A deposition., 2016; Molecular biology of the cell. 28(1) 54-64 PMID: 27807043 | PMCID: PMC5221629

Eagleson G, Pfister K, Knowlton AL, Skoglund P, Keller R, Stukenberg PT, Kif2a depletion generates chromosome segregation and pole coalescence defects in animal caps and inhibits gastrulation of the Xenopus embryo., 2015; Molecular biology of the cell. 26(5) 924-37 PMID: 25568341 | PMCID: PMC4342028

Stukenberg PT, Burke DJ, Connecting the microtubule attachment status of each kinetochore to cell cycle arrest through the spindle assembly checkpoint., 2015; Chromosoma. 124(4) 463-80 PMID: 25917595 |

Trivedi P, Stukenberg PT, A Centromere-Signaling Network Underlies the Coordination among Mitotic Events., 2015; Trends in biochemical sciences. 41(2) 160-74 PMID: 26705896 | PMCID: PMC4733523

Grant IM, Balcha D, Hao T, Shen Y, Trivedi P, Patrushev I, Fortriede JD, Karpinka JB, Liu L, Zorn AM, Stukenberg PT, Hill DE, Gilchrist MJ, The Xenopus ORFeome: A resource that enables functional genomics., 2015; Developmental biology. 408(2) 345-57 PMID: 26391338 | PMCID: PMC4684507

Krizaic I, Williams SJ, S?nchez P, Rodr?guez-Corsino M, Stukenberg PT, Losada A, The distinct functions of CENP-C and CENP-T/W in centromere propagation and function in Xenopus egg extracts., 2015; Nucleus (Austin, Tex.). 6(2) 133-43 PMID: 25569378 | PMCID: PMC4615894

Zy?kiewicz E, Stukenberg PT, Xenopus egg extracts as a simplified model system for structure-function studies of Dynein regulators., 2014; Methods in molecular biology (Clifton, N.J.). 1136() 117-33 PMID: 24633797 |

Matson DR, Stukenberg PT, CENP-I and Aurora B act as a molecular switch that ties RZZ/Mad1 recruitment to kinetochore attachment status., 2014; The Journal of cell biology. 205(4) 541-554 PMID: 24862574 | PMCID: PMC4033774

Banerjee B, Kestner CA, Stukenberg PT, EB1 enables spindle microtubules to regulate centromeric recruitment of Aurora B., 2014; The Journal of cell biology. 204(6) 947-63 PMID: 24616220 | PMCID: PMC3998792

Manukyan A, Ludwig K, Sanchez-Manchinelly S, Parsons SJ, Stukenberg PT, A complex of p190RhoGAP-A and anillin modulates RhoA-GTP and the cytokinetic furrow in human cells., 2014; Journal of cell science. 128(1) 50-60 PMID: 25359885 | PMCID: PMC4282047

Matson DR, Stukenberg PT, Cdt1 throws kinetochore-microtubule attachments for a loop., 2012; Nature cell biology. 14(6) 561-3 PMID: 22643874 | PMCID: PMC3600811

Matson DR, Demirel PB, Stukenberg PT, Burke DJ, A conserved role for COMA/CENP-H/I/N kinetochore proteins in the spindle checkpoint., 2012; Genes & development. 26(6) 542-7 PMID: 22426531 | PMCID: PMC3315115

Utepbergenov D, Derewenda U, Olekhnovich N, Szukalska G, Banerjee B, Hilinski MK, Lannigan DA, Stukenberg PT, Derewenda ZS, Insights into the inhibition of the p90 ribosomal S6 kinase (RSK) by the flavonol glycoside SL0101 from the 1.5 ? crystal structure of the N-terminal domain of RSK2 with bound inhibitor., 2012; Biochemistry. 51(33) 6499-510 PMID: 22846040 | PMCID: PMC3462495

Foltz DR, Stukenberg PT, A new histone at the centromere?, 2012; Cell. 148(3) 394-6 PMID: 22304909 | PMCID: PMC3404608

Niedzialkowska E, Wang F, Porebski PJ, Minor W, Higgins JM, Stukenberg PT, Molecular basis for phosphospecific recognition of histone H3 tails by Survivin paralogues at inner centromeres., 2012; Molecular biology of the cell. 23(8) 1457-66 PMID: 22357620 | PMCID: PMC3327328

Zy?kiewicz E, Kija?ska M, Choi WC, Derewenda U, Derewenda ZS, Stukenberg PT, The N-terminal coiled-coil of Ndel1 is a regulated scaffold that recruits LIS1 to dynein., 2011; The Journal of cell biology. 192(3) 433-45 PMID: 21282465 | PMCID: PMC3101096

Zheng M, Cierpicki T, Burdette AJ, Utepbergenov D, Janczyk P?, Derewenda U, Stukenberg PT, Caldwell KA, Derewenda ZS, Structural features and chaperone activity of the NudC protein family., 2011; Journal of molecular biology. 409(5) 722-41 PMID: 21530541 | PMCID: PMC3159028

Matson DR, Stukenberg PT, Spindle poisons and cell fate: a tale of two pathways., 2011; Molecular interventions. 11(2) 141-50 PMID: 21540474 | PMCID: PMC3086919

Tooley JG, Miller SA, Stukenberg PT, The Ndc80 complex uses a tripartite attachment point to couple microtubule depolymerization to chromosome movement., 2011; Molecular biology of the cell. 22(8) 1217-26 PMID: 21325630 | PMCID: PMC3078066

Tooley J, Stukenberg PT, The Ndc80 complex: integrating the kinetochore's many movements., 2011; Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology. 19(3) 377-91 PMID: 21311965 | PMCID: PMC3148027

Wang F, Dai J, Daum JR, Niedzialkowska E, Banerjee B, Stukenberg PT, Gorbsky GJ, Higgins JM, Histone H3 Thr-3 phosphorylation by Haspin positions Aurora B at centromeres in mitosis., 2010; Science (New York, N.Y.). 330(6001) 231-5 PMID: 20705812 | PMCID: PMC2967368

Stukenberg PT, Foltz DR, Kinetochores: orchestrating the chromosomal minuet., 2010; Current biology : CB. 20(12) R522-5 PMID: 20620907 | PMCID: PMC3148016

Fuller BG, Stukenberg PT, Cell division: righting the check., 2009; Current biology : CB. 19(14) R550-3 PMID: 19640489 | PMCID: PMC2880852

Wan X, O'Quinn RP, Pierce HL, Joglekar AP, Gall WE, DeLuca JG, Carroll CW, Liu ST, Yen TJ, McEwen BF, Stukenberg PT, Desai A, Salmon ED, Protein architecture of the human kinetochore microtubule attachment site., 2009; Cell. 137(4) 672-84 PMID: 19450515 | PMCID: PMC2699050

Knowlton AL, Vorozhko VV, Lan W, Gorbsky GJ, Stukenberg PT, ICIS and Aurora B coregulate the microtubule depolymerase Kif2a., 2009; Current biology : CB. 19(9) 758-63 PMID: 19327998 | PMCID: PMC2775053

Wang W, Stukenberg PT, Brautigan DL, Phosphatase inhibitor-2 balances protein phosphatase 1 and aurora B kinase for chromosome segregation and cytokinesis in human retinal epithelial cells., 2008; Molecular biology of the cell. 19(11) 4852-62 PMID: 18716057 | PMCID: PMC2575180

Fuller BG, Lampson MA, Foley EA, Rosasco-Nitcher S, Le KV, Tobelmann P, Brautigan DL, Stukenberg PT, Kapoor TM, Midzone activation of aurora B in anaphase produces an intracellular phosphorylation gradient., 2008; Nature. 453(7198) 1132-6 PMID: 18463638 | PMCID: PMC2724008

Burke DJ, Stukenberg PT, Linking kinetochore-microtubule binding to the spindle checkpoint., 2008; Developmental cell. 14(4) 474-9 PMID: 18410725 | PMCID: PMC2696048

Ahonen LJ, Kukkonen AM, Pouwels J, Bolton MA, Jingle CD, Stukenberg PT, Kallio MJ, Perturbation of Incenp function impedes anaphase chromatid movements and chromosomal passenger protein flux at centromeres., 2008; Chromosoma. 118(1) 71-84 PMID: 18784935 | PMCID: PMC3442196

Miller SA, Johnson ML, Stukenberg PT, Kinetochore attachments require an interaction between unstructured tails on microtubules and Ndc80(Hec1)., 2008; Current biology : CB. 18(22) 1785-91 PMID: 19026542 | PMCID: PMC3145211

Emanuele MJ, Lan W, Jwa M, Miller SA, Chan CS, Stukenberg PT, Aurora B kinase and protein phosphatase 1 have opposing roles in modulating kinetochore assembly., 2008; The Journal of cell biology. 181(2) 241-54 PMID: 18426974 | PMCID: PMC2315672

Rosasco-Nitcher SE, Lan W, Khorasanizadeh S, Stukenberg PT, Centromeric Aurora-B activation requires TD-60, microtubules, and substrate priming phosphorylation., 2008; Science (New York, N.Y.). 319(5862) 469-72 PMID: 18218899 |

Emanuele M, Burke DJ, Stukenberg PT, A Hec of a microtubule attachment., 2007; Nature structural & molecular biology. 14(1) 11-3 PMID: 17203069 | PMCID: 17203069

Vorozhko VV, Emanuele MJ, Kallio MJ, Stukenberg PT, Gorbsky GJ, Multiple mechanisms of chromosome movement in vertebrate cells mediated through the Ndc80 complex and dynein/dynactin., 2007; Chromosoma. 117(2) 169-79 PMID: 18057949 | PMCID: PMC2522317

Zhang X, Lan W, Ems-McClung SC, Stukenberg PT, Walczak CE, Aurora B phosphorylates multiple sites on mitotic centromere-associated kinesin to spatially and temporally regulate its function., 2007; Molecular biology of the cell. 18(9) 3264-76 PMID: 17567953 | PMCID: PMC1951741

Potapova TA, Daum JR, Pittman BD, Hudson JR, Jones TN, Satinover DL, Stukenberg PT, Gorbsky GJ, The reversibility of mitotic exit in vertebrate cells., 2006; Nature. 440(7086) 954-8 PMID: 16612388 | PMCID: PMC1513549

Resnick TD, Satinover DL, MacIsaac F, Stukenberg PT, Earnshaw WC, Orr-Weaver TL, Carmena M, INCENP and Aurora B promote meiotic sister chromatid cohesion through localization of the Shugoshin MEI-S332 in Drosophila., 2006; Developmental cell. 11(1) 57-68 PMID: 16824953 |