Heads of Laboratories
Pels Family Professor
Selma and Lawrence Ruben Laboratory of Chemistry and Cell Biology
A cell’s ability to accurately segregate genetic material during division is essential for the survival of an organism, and errors can result in developmental defects and diseases. Dr. Kapoor’s laboratory works at the interface of chemistry and biology to investigate the molecular and physical mechanisms that explain how exactly one copy of the genome is delivered to each daughter cell during cell division.
Human cells divide approximately 10,000 trillion times during a lifetime. During cell division, cells must suspend DNA repair, protein synthesis, and other essential activities. As a result, cells need to complete cell division quickly and precisely; in human cells, this process requires only an hour. If the metaphase spindle does not properly separate the parent cell’s DNA to the two daughter cells, diseases, such as cancer, and developmental defects, such as Down syndrome, may result. Dr. Kapoor is interested in understanding the fundamental mechanisms that allow cells to achieve this delicate balance between speed and accuracy.
The complex, sequential, and rapid nature of this process makes it difficult to study, and, because of the limitations of conventional approaches, several basic questions about the operation and function of the mitotic spindle remain unanswered. Typically, researchers must choose either whole-system studies that do not offer precise insight into biochemical details or studies of proteins in isolation and out of their physiological context. Dr. Kapoor develops chemistry-based approaches to close this gap.
His lab has discovered and synthesized small organic molecules that can enter cells and interfere with cell division processes within minutes or seconds. The effect of these inhibitors can then be reversed to see how the cell recovers. This reversible “shutting off” of a process at a precise time point can be challenging to perform with other approaches. Dr. Kapoor’s lab is currently working to identify chemicals that can interfere with the assembly of microtubule-based structures. For instance, Dr. Kapoor and colleagues identified small molecules known as ciliobrevins. They used these to block the activity of the motor protein cytoplasmic dynein, which is involved in many cellular processes. This discovery allowed them to probe cytoplasmic dynein’s role in ciliary trafficking, mitotic spindle formation, and organelle transport.
In addition to developing methods for the discovery, chemical synthesis, and characterization of bioactive small molecules, Dr. Kapoor is establishing assays to study how the cell assembles the micron-scale structures necessary for cell division. These structures are the product of nanometer-sized proteins decoding micron-sized geometric attributes, such as microtubule length and orientation. In recent work, Dr. Kapoor’s lab has shown how two proteins, PRC1 and kinesin-4, mark the plus ends of microtubules with tags proportional to the length of the microtubules but one thousand times bigger than PRC1 and kinesin-4. These tags may help the cell select and organize microtubules to position the cell division plane and keep chromosomes segregated during the final stages of division.
The quest to better understand cell division has immediate implications for medicine because it can lead to the development of therapies for diseases associated with improper division. In addition, the small-molecule probes Dr. Kapoor and his lab members identified have the potential to serve as templates for drugs and to help validate new targets for chemotherapeutics.
Kapoor is a faculty member in the David Rockefeller Graduate Program, the Tri-Institutional M.D.-Ph.D. Program, and the Tri-Institutional Ph.D. Program in Chemical Biology.
B.S. in chemistry and biology, 1993
California Institute of Technology
M.S. in chemistry, 1994
Ph.D. in chemistry, 1998
Harvard Medical School, 1998–2001
Assistant Professor, 2001–2005
Associate Professor, 2005–2008
The Rockefeller University
Pew Biomedical Scholar, 2003
Leukemia and Lymphoma Society Scholar, 2008
Irving Sigal Young Investigator Award, The Protein Society, 2012
Subramanian, R. et al. Marking and measuring single microtubules by PRC1 and kinesin-4. Cell 154, 377–390 (2013).
Kleiner, R.E. et al. Site-specific chemistry on the microtubule polymer. J. Am. Chem. Soc. 135, 12520–12523 (2013).
Firestone, A.J. et al. Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein. Nature 484, 125–129 (2012).
Wacker, S.A. et al. Using transcriptome sequencing to identify mechanisms of drug action and resistance. Nat. Chem. Biol. 8, 235–237 (2012).
Shimamoto, Y. et al. Insights into the micromechanical properties of the metaphase spindle. Cell 145, 1062–1074 (2011).
Dr. Kapoor is a faculty member in the David Rockefeller Graduate Program, the Tri-Institutional M.D.-Ph.D. Program, and the Tri-Institutional Ph.D. Program in Chemical Biology.