Our research focuses on the control of genome stability. As our cells grow and prepare to proliferate they must first accurately duplicate the entire genome and then segregate the copies into two exact and complete sets as the cell divides into two. Errors in either of these processes generate genetic alterations that underlie infertility, developmental defects, and cancer. Multiple regulatory mechanisms, many of which rely on the interplay between ubiquitin ligases and cellular checkpoints, ensure the fidelity of these essential processes. Oncogene activity places increased stress on genome duplication and segregation machinery and subsequently a higher demand on the checkpoints that monitor them. Exploiting this inherent weakness by attacking these processes to induce additional stress is a proven therapeutic strategy. By identifying novel factors and delineating how cells (both normal and cancerous) maintain genome stability and deal with intrinsic and extrinsic barriers to this goal we will gain important insight into the evolution of tumor cells and an improved understanding of how cells respond to current therapeutics. Together this knowledge may direct more effective use of current therapies and has the potential to identify new therapeutic targets and strategies that more specifically target cancer cells. We currently have two main projects:
In the first project, we are continuing to examine the role of the deubiquitinating enzyme USP37 in the regulation of replication and the cell cycle. Dysregulation of USP37 has been implicated in cancer, but whether it plays oncogenic or tumor suppressive role is unclear and may be context specific. We have found that multi-faceted regulation limits USP37 expression and activity to S/G2. During this time USP37 interacts with the APCCdh1 and SCFβTrCP ubiquitin ligases, which control multiple aspects of genome duplication and stability. We now seek to identify additional targets of USP37 to understand how it influences the interplay of these ligases, the role it plays in genome maintenance, and determine its potential to impact cancer therapy.
The second project focuses on the regulation of chromosome segregation in mitosis. The spindle assembly checkpoint (SAC) halts mitotic progression by inhibiting the APCCdc20 ubiquitin ligase to ensure that chromosomes are accurately segregated and is also a central mediator of anti-mitotic chemotherapeutics such as Taxol. In order for cells to resume mitosis and divide the generation of APCCdc20-inhibitory complexes must be halted and the existing complexes disassembled. Our recent work suggests that SAC-silencing is a highly dynamic and regulated process, which is likely to be altered in cancer. We are now defining the network of factors that control this process and dissecting the mechanisms by which they antagonize the checkpoint. We anticipate that these studies will provide important insight into chromosome missegregation as well as mechanisms of resistance to Taxol or other anti-mitotics.
The loss of internal controls that limit and regulate cell growth is a hallmark of cancer cells. Although cancer cells tolerate certain levels of changes to their DNA they must retain the blueprints for building the machinery required for cell growth and survival. Thus, they must still duplicate and transmit their genomes from one generation to the next with minimal errors in order for the tumor to continue to grow. The checkpoints that monitor these processes are rarely defective in cancer cells and are often highly active due to the loss of other control mechanisms. By inducing additional stress and/or inhibiting these remaining checkpoints we can induce death in tumors. The goal of our research is to understand how cancer cells overcome their internal stress and cope with drug-induced stress to guide the development of improved therapeutic strategies.
Date DA, Burrows AC, and Summers MK. Phosphorylation regulates the p31Comet – Mad2 interaction to promote Spindle Assembly Checkpoint (SAC) activity. J. Biol. Chem. 2014 April 18;289(16): 11367-73
Date DA, Burrows AC, Venere M, Jackson MW, Summers MK. Coordinated regulation of p31Comet and Mad2 expression is required for cellular proliferation. Cell Cycle. 2013 Oct 15;12(24). PMID: 24131926
Giovinazzi S, Morozov MV, Summers MK, Reinhold WC, and Ishov AM. USP7 and Daxx regulate mitosis progression and taxanes sensitivity by affecting stability of Aurora A kinase. Cell Death Differ. 2013 Jan 25 (Epub ahead of print).
Burrows AC, Prokop J, and Summers MK. Skp1-Cul1-F-box Ubiquitin Ligase (SCFβTrCP)-Mediated Destruction of the Ubiquitin-Specific Protease USP37 During G2-Phase Promotes Mitotic Entry. J. Biol. Chem. 2012 Nov 9;287(46):39021-9 PMID: 23027877
Torres JZ, Summers MK, Peterson D, Brauer MJ, Lee J, Senese S, Gholkar AA, Lo YC, Lei X, Jung K, Anderson DC, Belmont L, and Jackson PK. The STARD9/Kif16a Kinesin Associates with Mitotic Microtubules and Regulates Spindle Pole Assembly, Cell, 2011 Dec 9;147(6):1309-23 PMID: 22153075
Giovinazzi S, Lindsay CR, Morozov VM, Escobar-Cabrera E, Summers MK, Han HS, McIntosh LP, and Ishov AM. Regulation of mitosis and taxane response by Daxx and Rassf1. Oncogene, 2011 June 6. (Epub ahead of print) PMID: 21643015
Huang X, Summers MK, Pham V, Lill JR, Liu J, Lee G, Kirkpatrick DS, Jackson PK, Fang G, Dixit VM. Deubiquitinase USP37 is activated by CDK2 to antagonize APCCDH1 and promote S-phase entry. Mol.Cell, 2011 May 20;42(4):511-523
Summers MK, Pan B, Mukhyala K, Jackson PK. The unique N-terminus of the UbcH10 E2 enzyme controls the threshold for APC activation and enhances checkpoint regulation of the APC. Mol Cell. 2008 Aug 22;31(4):544-56
Keck JM, Summers MK, Tedesco D, Ekholm-Reed S, Chuang L, Jackson PK, and Reed SI. Cyclin E deregulation impairs progression through mitosis by inhibiting APCCdh1. J. Cell Biol. 2007 July; 138(3):371-385
Miller JJ, Summers MK, Hansen DV, Nachury MV, Lehman NL, Loktev A, Jackson PK. Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor. Genes Dev. 2006 Sep 1;20(17):2410-20
Summers MK, Bothos J, and Halazonetis TD. The Chfr mitotic checkpoint protein arrests cells in early prophase with partially depolymerized lamins and cytoplasmic Cyclin B1. Oncogene, 2005 Apr 14;24(16):2589-98