The David H. Koch Institute for Integrative Cancer Research at MITThe David H. Koch Institute for Integrative Cancer Research at MIT

Massachusetts Institute of Technology

National Cancer Institute Cancer Center

Science + Engineering... Conquering Cancer Together

Angelika Amon, PhD

Angelika Amon is Kathleen and Curtis Marble Professor in Cancer Research and Professor of Biology

Kathleen and Curtis Marble Professor in Cancer Research

Professor of Biology

Investigator, Howard Hughes Medical Institute

 

KI Research Areas of Focus:
Metastasis, Personalized Medicine, Cancer Immunology

"We study the molecular mechanisms that govern chromosome segregation and the consequences – aneuploidy – when these fail. In our work on chromosome segregation, we focus on mechanisms that control final stages of mitosis using budding yeast as a model system. We also investigate what happens in cells where chromosome segregation mechanisms fail and that become aneuploid. We study the effects of aneuploidy on cellular physiology and how the condition contributes to cancer. We also explore how the vulnerabilities associated with aneuploidy could be exploited for new tumor therapies."

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. In 2019 she was named the recipient of the Vilcek Prize in Biomedical Science and a winner of the Breakthrough Prize in Life Sciences.

Further Information

Research Summary

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.

Regulation of meiotic chromosome segregation

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:

  1. Reciprocal recombination between homologous chromosomes creates physical linkages between homologs, allowing them to stably align on the metaphase I spindle.
  2. Stepwise loss of cohesin complexes occurs from chromosome arms during meiosis I and from centromeric regions during meiosis II.
  3. Kinetochore orientation changes during meiosis. Sister kinetochores attach to microtubules so that they face the same spindle pole (co-orientation) during meiosis I. This facilitates homolog separation. During meiosis II sister kinetochores attach to microtubules emanating from opposite poles (bi-orientation). This allows sister chromatids to separate.

Stepwise loss of cohesins during meiosis

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.

Sister kinetochore orientation during meiosis

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.

Regulation of the meiosis I – meiosis II transition

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.

Selected Publications

Neurohr GE, Terry RL, Lengefeld J, Bonney M, Brittingham GP, Moretto F, Miettinen TP, Vaites LP, Soares LM, Paulo JA, Harper JW, Buratowski S, Manalis S, van Werven FJ, Holt LJ, Amon A. Excessive cell growth causes cytoplasm dilution and contributes to senescence. Cell. 2019 Feb 21;176(5):1083-1097.e18.

Knouse KA, Lopez KE, Bachofner M, Amon A. Chromosome segregation fidelity in epithelia requires tissue architecture. Cell. 2018 Aug 17. pii: S0092-8674 (18)30970-X.

Weidberg H, Amon A. MitoCPR-A surveillance pathway that protects mitochondria in response to protein import stress. Science. 2018 Apr 13;360(6385). pii: eaan4146.

Tang YC, Yuwen H, Wang K, Bruno PM, Bullock K, Deik A, Santaguida S, Trakala M, Pfau SJ, Zhong N, Huang T, Wang L, Clish CB, Hemann MT, Amon A. Aneuploid cell survival relies upon sphingolipid homeostasis. Cancer Res. 2017 Oct 1;77(19):5272-5286.  

Santaguida S, Richardson A, Iyer DR, M'Saad O, Zasadil L, Knouse KA, Wong YL, Rhind N, Desai A, Amon A. Chromosome mis-segregation generates cell-cycle-arrested cells with complex karyotypes that are eliminated by the immune system. Dev Cell. 2017 Jun 19;41(6):638-651.e5.

Beach RR, Ricci-Tam C, Brennan CM, Moomau CA, Hsu P-H, Hua B, Silberman RE, Springer M, Amon A. Aneuploidy causes non-genetic individuality. Cell. 2017 Apr 6;169(2):229–242.e21.

Sheltzer JM, Ko JH, Replogle JM, Habibe Burgos NC, Chung ES, Meehl CM, Sayles NM, Passerini V, Storchova Z, Amon A. Single-chromosome gains commonly function as tumor suppressors. Cancer Cell. 2017 Feb 13;31(2):240–255.

Pfau SJ, Silberman RE, Knouse KA, Amon A. Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo. Genes Dev. 2016 Jun 15;30(12):1395-408.

Knouse KA, Wu J, Whittaker CA, Amon A. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci U S A. 2014 Sep 16; 111(37): 13409-11344.

Tang YC, Williams BR, Siegel JJ, Amon A. Identification of aneuploidy-selective antiproliferation compounds. Cell. 2011 Feb 18; 144(4): 499-512. PMCID: PMC3532042

Attner MA, Miller MP, Ee LS, Elkin SK, Amon A. Polo kinase Cdc5 is a central regulator of meiosis I. Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14278-14283. PMCID: PMC3761645

Elledge SJ, Amon A. The BRCA1 suppressor hypothesis: an explanation for the tissue-specific tumor development in BRCA1 patients. Cancer Cell. 2002 Mar; 1(2): 129-132.

Search PubMed for Amon lab publications

Contact Information

Angelika Amon

room 76-561
phone (617) 258-8964
email angelika@mit.edu

Amon Lab

phone (617) 253-3045
fax (617) 258-6558
website

Administrative Coordinator:

Erica Burds
phone (617) 258-6559
email ericarie@mit.edu