The long-term goal of this grant is to elucidate the molecules and mechanisms that sustain the accuracy of chromosome segregation. Such information is crucial for maintaining and improving human health, as inaccurate segregation causes aneuploidy and contributes to disorders like Down Syndrome and cancer. To facilitate the dissection of this and other complex biological processes, our laboratory has developed novel methods for precisely deleting or modifying genes in human somatic cells via homologous recombination. By combining these methods with high-resolution microscopy and chemical genetics, we have identified novel functions and regulation of the protein kinases Plk1 (Polo-like kinase 1) and Mps1, which are essential regulators of mitosis and cell division in all eukaryotes. Based on our preliminary findings, three aims are proposed for the next grant period: (1) to elucidate the effectors and mechanism of Plk1-dependent centrosome maturation;(2) to test Mps1's contribution to the cytosolic and kinetochore-dependent branches of the spindle assembly checkpoint (SAC);and (3) to identify the substrates of Mps1 that mediate the kinase's functions in SAC enforcement and chromosome bi-orientation. These studies will illuminate the mechanisms that regulate and sustain the high fidelity of chromosome segregation in humans. Such information is crucial for understanding how normal cells avoid aneuploidy and its adverse impacts on human health, and for developing novel treatments that specifically target aneuploidy in the context of disease.

Public Health Relevance

Errors in chromosome segregation result in aneuploidy, an abnormal genetic configuration strongly associated with human disease, including Down Syndrome and cancer. There is a strong need to elucidate how chromosome segregation is controlled at the molecular level, both to reduce the likelihood of aneuploidy in normal cells, and to exploit aneuploidy as an """"""""Achilles heel"""""""" in cancer cells. During the next grant period we focus specifically on the roles of two master kinases - Plk1 and Mps1 - in human chromosome segregation. As these kinases are overproduced in tumors and being evaluated as targets for anti-neoplastic therapy, our studies have strong relevance to ongoing efforts to expand and improve the cancer pharmacopeia.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM094972-08
Application #
8286240
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Hamlet, Michelle R
Project Start
2005-07-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$387,432
Indirect Cost
$184,482
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Kim, Minhee; O'Rourke, Brian P; Soni, Rajesh Kumar et al. (2016) Promotion and Suppression of Centriole Duplication Are Catalytically Coupled through PLK4 to Ensure Centriole Homeostasis. Cell Rep 16:1195-203
Chen, Yu-Hung; Jones, Mathew J K; Yin, Yandong et al. (2015) ATR-mediated phosphorylation of FANCI regulates dormant origin firing in response to replication stress. Mol Cell 58:323-38
Rahman, Sadia; Jones, Mathew J K; Jallepalli, Prasad V (2015) Cohesin recruits the Esco1 acetyltransferase genome wide to repress transcription and promote cohesion in somatic cells. Proc Natl Acad Sci U S A 112:11270-5
Pagan, Julia K; Marzio, Antonio; Jones, Mathew J K et al. (2015) Degradation of Cep68 and PCNT cleavage mediate Cep215 removal from the PCM to allow centriole separation, disengagement and licensing. Nat Cell Biol 17:31-43
Rodriguez-Bravo, Veronica; Maciejowski, John; Corona, Jennifer et al. (2014) Nuclear pores protect genome integrity by assembling a premitotic and Mad1-dependent anaphase inhibitor. Cell 156:1017-31
Jones, Mathew J K; Jallepalli, Prasad V (2012) Chromothripsis: chromosomes in crisis. Dev Cell 23:908-17
Oppermann, Felix S; Grundner-Culemann, Kathrin; Kumar, Chanchal et al. (2012) Combination of chemical genetics and phosphoproteomics for kinase signaling analysis enables confident identification of cellular downstream targets. Mol Cell Proteomics 11:O111.012351
Burkard, Mark E; Santamaria, Anna; Jallepalli, Prasad V (2012) Enabling and disabling polo-like kinase 1 inhibition through chemical genetics. ACS Chem Biol 7:978-81
Paschal, Catherine Randall; Maciejowski, John; Jallepalli, Prasad V (2012) A stringent requirement for Plk1 T210 phosphorylation during K-fiber assembly and chromosome congression. Chromosoma 121:565-72
Maciejowski, John; George, Kelly A; Terret, Marie-Emilie et al. (2010) Mps1 directs the assembly of Cdc20 inhibitory complexes during interphase and mitosis to control M phase timing and spindle checkpoint signaling. J Cell Biol 190:89-100

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