Summers Lab

Research Area

Mitosis, mitotic checkpoint, replication, replication stress, replication checkpoint, DNA damage, chromosomal instability, genomic instability, Ubiquitin Proteasome System, deubiquitinating enzymes, cell cycle checkpoints, therapeutic resistance, oncogene-induced stress

Research Summary

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, it 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.