The loss of cell cycle control is the most recognized trait of cancer cells. The ability of cells to exit the cell cycle has recently been shown to be dependent upon a large multi-protein repressor complex called DREAM. This complex represses the expression of all cell cycle genes during reversible cell cycle exit. In cycling cell, DREAM is disassembled and some of DREAM associated proteins form a new complex to promote cell cycle gene expression. These proteins that can act together both as repressors and activators of cell cycle gene expression are called the MuvB core. The MuvB core interacts with B-Myb during S phase to promote late cell cycle gene expression. This activator complex is called MMB and its integrity is required for proper cell division. The purpose of this project is t determine how the MuvB core interacts with B-Myb, and if MuvB can be targeted by therapeutics to restore proper cell cycle control in cancer. We have structurally and functionally characterized the mechanism of DREAM assembly and regulation, however MMB regulation remains poorly understood. DREAM has been suggested as a therapeutic target in cancer cells that arrest in response to drug treatment to evade apoptosis. Disruption of DREAM could force evasive cancer cells back into the cell cycle and elicit a response to chemotherapeutic treatment. Until recently, a DREAM interface to target was unavailable. I solved the x-ray crystal structure of MuvB core protein LIN52 complexed with RB tumor suppressor protein p107 and functionally characterized how this interaction is regulated in DREAM assembly. This is a suitable DREAM interface to target given disruption of this interface drives cell cycle entry. I have found that LIN52 also interacts with B-Myb. Therefore, I hypothesize that the MuvB core protein LIN52 mediates interactions with various transcription factors throughout the cell cycle to drive gene specificity through cooperative binding. I will test this hypothesis with two aims: 1) solve the X-ray crystal structure of B-Myb complexed with the MuvB core and investigate the cooperative DNA binding of MuvB and B-Myb; 2) Disrupt LIN52 interactions to disassemble DREAM in drug resistant cancer cells. Completion of these aims will unveil the mechanism of Myb activation in cancer and determine if LIN52 is a viable cancer therapeutic target.
The loss of cell cycle control is a hallmark of cancer. The loss of control occurs either through the direct mutation of cell cycle genes, or through aberrant expression of these genes. All cell cycle gene expression is regulated by a protein complex called MuvB. The focus of this project is to determine how MuvB regulates gene expression and how it could be targeted by therapeutics to restore cell cycle control in cancer cells.
| Guiley, Keelan Z; Iness, Audra N; Saini, Siddharth et al. (2018) Structural mechanism of Myb-MuvB assembly. Proc Natl Acad Sci U S A 115:10016-10021 |
