Kathleen and Curtis Marble Professor in Cancer Research
Professor of Biology
Investigator, Howard Hughes Medical Institute
"Our laboratory brings a deep expertise in the process by which normal healthy cells divide and proliferate to the problem of cancer. Cell division is the fundamental process by which an organism is built. Deciphering the regulatory networks that govern cell division is therefore vital to understanding both normal cell division and the abnormal cell division that is a hallmark of cancer. We study the mechanisms that control the transitions from one cell-cycle stage to the next using budding yeast as a model system. We focus on how the anaphase–G1 transition, also known as exit from mitosis, is regulated and integrated with other cell cycle events and on how a specialized cell cycle, the meiotic cell cycle is established. These studies will hopefully shed light on the causes of meiotic chromosome mis-segregation, the leading cause of miscarriages in humans."
Learn more about the Amon lab and how understanding cell division and cell stress may lead to the development of new drugs or compounds that selectively kill cancer cells by watching this video: "Inside the Lab: Angelika Amon, Ph.D."
A molecular and cell biologist, Dr. Amon is the Kathleen and Curtis Marble Professor in Cancer Research and Professor of Biology at MIT. She received her B.S. from the University of Vienna and continued her doctoral work there under Professor Kim Nasmyth at the Research Institute of Molecular Pathology, receiving her Ph.D. in 1993. She completed a two-year post-doctoral fellowship at the Whitehead Institute in Cambridge, Massachusetts and was subsequently named a Whitehead Fellow for three years. In 1999, she joined the MIT Center for Cancer Research and the Department of Biology and was promoted to full Professor in 2007. Dr. Amon has won a Presidential Early Career Award for Scientists and Engineers in 1998, was named an Associate Investigator at the Howard Hughes Medical Institute in 2000, and was the 2003 recipient of the National Science Foundation's Alan T. Waterman Award. She has also shared the 2007 Paul Marks Prize for Cancer Research and won the 2008 National Academy of Sciences Award in Molecular Biology. In 2013, Dr. Amon was awarded the Ernst Jung Prize for medicine, one of Europe’s most prestigious and generous medical awards, and was recently named as a winner of the 2019 Breakthrough Prize in Life Sciences.
For budding yeast cells to leave mitosis and enter the next G1 phase the protein phosphatase Cdc14 needs to be activated. This activation step involves the dissociation of Cdc14 from an inhibitory subunit Cfi1/Net1, which binds to and sequesters the phosphatase in the nucleolus during G1, S phase and early mitosis. During anaphase Cdc14 is released from its inhibitor allowing it to become active and to bring about exit from mitosis. Two regulatory networks have been identified that control the association of Cdc14 with Cfi1/Net1. The Cdc14 early anaphase release network (FEAR network) promotes Cdc14 release from the nucleolus during early anaphase, whereas the Mitotic Exit Network (MEN) maintains Cdc14 in a released state during late stages of anaphase and telophase.
The FEAR network is comprised of several proteins that are not only important for mitotic exit but also for chromosome segregation during anaphase. Currently, the Amon lab is investigating how FEAR network components function to promote Cdc14 release from the nucleolus and how the FEAR network couples exit from mitosis to chromosome segregation. The second signaling pathway that controls Cdc14 activity, the Mitotic Exit Network resembles a Ras-like signaling cascade. The Amon lab studies on signals controlling the activity of the MEN revealed that this pathway ensures that cells exit from mitosis only after the nucleus has been partitioned between the future daughter cells. The MEN senses nuclear position in part due to physical separation of the GTPase Tem1 and its activator Lte1 prior to exit from mitosis. Tem1's GAP Bub2 also contributed to restraining mitotic exit when the nucleus is not partitioned between the two future daughter cells. Currently, the Amon lab is investigating how the protein kinase Kin4 affects the activity of Bub2 in response to nuclear position defects.
In addition to studying how Cdc14 is regulated, the lab investigated the function of this phosphatase during mitosis. Cdc14's main role is to reverse CDK phosphorylation events thereby triggering exit from mitosis. Recent studies in the lab showed that Cdc14 also regulates the segregation of repetitive DNA. Chromosome segregation requires the Separase-dependent removal of cohesin complexes, which link sister chromatids. Their findings show that the segregation of specialized chromosomal domains requires mechanisms in addition to cohesin removal. Late segregating DNA elements, such as the telomeres and the rDNA, also require Cdc14 activated by the FEAR network for proper segregation. Cdc14 promotes the enrichment of condensins, which are protein complexes required for chromosome condensation and rDNA segregation, at this locus. The fact that Cdc14 promotes the partitioning of late-segregating DNA regions as well as exit from mitosis provides a mechanism for ensuring that sister-chromatid separation is completed before cells exit from mitosis.
Meiosis is a specialized cell cycle that leads to the formation of gametes. Defects in meiotic chromosome segregation are the leading cause of miscarriages and one of the leading causes of birth defects in humans. Understanding how meiotic chromosome segregation is regulated and how the mitotic chromosome segregation cycle is modulated to bring about the specialized meiotic chromosome segregation program is, thus, crucial to uncover the molecular causes of chromosome mis-segregation during meiosis.
During the meiotic cell cycle a single S-phase is followed by two consecutive nuclear divisions. During meiosis I, separation of homologous chromosomes occurs; segregation of sister chromatids takes place during meiosis II. For the meiotic chromosome segregation program to succeed, three meiosis-specific events need to take place:
To identify genes required for the stepwise loss of cohesins from chromosomes, the Amon lab performed a screen in which they analyzed the segregation pattern of a GFP-marked chromosome III in a collection of yeast strains in which individual genes were deleted (yeast knock-out collection). Several mutants were isolated that lose centromeric cohesins prematurely (that is during meiosis I rather than during meiosis II). The affected genes (IML3, CHL4 and SGO1) were shown to be required for protecting centromeric cohesins during meiosis I and their gene products to localize to kinetochores during meiosis.
The meiosis-specific factor Spo13 also regulates cohesin removal. Spo13 was known to be essential for establishing the meiosis I chromosome segregation pattern. The Amon lab and others subsequently showed that SPO13 was required to protect centromeric cohesins from removal during meiosis I. Furthermore, Spo13 when overproduced, inhibits cleavage of cohesin, raising the interesting possibility that SPO13 protects cohesin from Separase activity. This mechanism would provide a molecular basis for how cohesin removal from centromeric regions is prevented during meiosis I. Currently researchers in the Amon lab are investigating how Iml3, Chl4, Sgo1 and Spo13 protect centromeric cohesins from removal during meiosis I.
By generating meiosis-specific loss-of-function alleles, the Amon lab researchers were able to characterize the role of the polo kinase Cdc5 during meiosis. They found that this protein kinase is required for kinetochore co-orientation during meiosis I. In the absence of CDC5, sister kinetochores attach to microtubules emanating from opposite poles rather than the same pole. In addition, proteins required for proper kinetochore orientation, such as Mam1, were mis-localized in Cdc5-depleted cells. SPO13 was also required for kinetochore co-orientation during meiosis I and for Mam1 to localize to kinetochores. How Cdc5 and Spo13 promote the association of Mam1 with kinetochores is an important problem that they plan to address.
During meiosis two successive chromosome-segregation phases occur with no intervening S phase. Thus, conditions have to be established at the end of the first division that allow a second round of chromosome segregation and simultaneously inhibit S phase. Studies by the Amon lab indicate that Cdc14 and the FEAR network are instrumental in this process. Cells impaired for FEAR network or CDC14 function fail to exit from the first meiotic division but meiosis II events continue to occur. Thus, Cdc14 and the FEAR network play a central role in creating two consecutive chromosome segregation phases, a key feature of the meiotic cell cycle.
D'Aquino, K. E., Monje-Casas, F., Paulson, J., Reiser, V., Charles, G. M., Lai, L., Shokat, K. M., and Amon, A. (2005). The protein kinase Kin4 inhibits exit from mitosis in response to spindle position defects. Mol. Cell 19, 223-234.
Hochwagen, A., Tham, W. H., Brar, G. A. and Amon A. (2005). The FK506 binding protein Fpr3 counteracts protein phosphatase 1 to maintain meiotic recombination checkpoint activity. Cell 122, 861-873.
Kiburz B. M, Reynolds, D. B., Megee, P. C., Marston, A. L., Lee, B. H., Lee, T. I., Levine, S. S., Young, R. A. and Amon A. (2005). The core centromere and Sgo1 establish a 50-kb cohesin-protected domain around centromeres during meiosis I. Genes Dev. 19, 3017-3030.
Lee, B.H., and Amon, A. (2003). Role of Polo-like kinase CDC5 in programming meiosis I chromosome segregation. Science 300, 482-486.
Marston, A. L., Lee, B. H. and Amon, A. The Cdc14 phosphatase and the FEAR network control meiotic spindle disassembly and chromosome segregation. Dev. Cell 4, 711-726. (2003).
Marston, A. L., Tham, W.-H., Shah, H. and Amon, A. (2004). A genome-wide screen identifies genes required for centromeric cohesion. Science 303, 1367-1370.
Stegmeier, F., Huang, J., Rahal, R., Zmolik, J., Moazed, D. and Amon, A. (2004). The replication fork block protein Fob1 functions as a negative regulator of the FEAR network. Curr. Bio. 14, 467-480