The work in the lab focuses on two main lines of investigation.
1) Elucidating the mechanism and functional importance of the regulation of the cell cycle transcriptional program by the checkpoints that ensure the maintenance of genome integrity.
2) Obtaining a better understanding of fundamental regulatory pathways that cause changes in cell-cycle regulated gene expression and the importance of this regulation for the maintenance of genome integrity.
Our work is aimed at helping explain, at the molecular level, why defects in proteins ranging from gene-specific transcriptional regulators to global regulators of transcription are associated with human disease most notably cancer.
Cell cycle regulated transcription and control of genome integrity.
Life starts with one cell, a fertilized egg. This one cell will multiply, through cell division, and change into all the different cells needed to make a whole, complicated organism such as a human being. This astonishing process requires tight control of all cell divisions taking place during development and throughout the life of for example a human being. This regulation is controlled by several ‘cell cycle checkpoints’ that ensure no mistakes are made before a cell is allowed to progress through the cell cycle in order to divide.
Cancer is a group of diseases in which cells continue to multiply in an unregulated manner as a result of checkpoint failure. Initiation of the cell division cycle in human cells is imposed during the G1-phase of the cell cycle. Activation of a large group of cell cycle dependent transcripts in G1 drives entry into the next phase of the cell cycle, S phase, and thereby committing cells to a new cell division cycle. The high frequency of genetic alterations that affect proteins involved in G1/S transcriptional regulation detected in human tumor cells illustrates the importance of this regulation for faithful cell proliferation.
Yeast as a model for human cells, human cells as a model for cancer.
We utilize the model organisms budding yeast, Saccharomyces cerevisiae and the distantly related fission yeast, Schizosaccharomyces pombe, to identify basic molecular mechanisms involved in transcriptional regulation during the cell-cycle and in response to genotoxic stress. In addition, using the insight obtained from past and ongoing work in yeast as a guide, we direct efforts to elucidate the mechanism and functional importance of this regulation in human cells.
The role of E2F activity in oncogene-induced replication stress.
Oncogenes, such as Ras, c-myc and CyclinE, deregulate E2F-dependent G1/S transcription to drive passage into S-phase and cell proliferation. By accelerating S-phase entry, these oncogenes also generate replication stress a crucial driver of genomic instability and one of the key events contributing to the onset of cancer. Whilst this suggests a direct link between E2F deregulation and oncogene-induced replication stress, our recent work indicates that cells experiencing replication stress also rely on E2F-dependent transcription to prevent replication stress-induced DNA damage. Based on our findings we propose a model in which cells that experience oncogene-induced replication stress become addicted to E2F activity to cope with high levels of replication stress, exposing a potential therapeutic window to target specific cancer cells.
Exploit cancer’s addiction to deregulated G1/S transcription.
The overall aim of our work our CRUK funded work is to provide a comprehensive understanding of the role of E2F-dependent transcription in the underlying mechanism of oncogene-induced replication stress and tolerance. The correlation between E2F deregulation and replication stress during oncogene transformation might provide clear markers for tumor progression and intra-tumor heterogeneity. This could guide the best treatment strategy based on specific deregulation of replication-initiation. Identification of E2F target proteins involved in replication stress tolerance will provide potential anti-cancer drug targets. Inactivation of these proteins is expected to affect the protective buffer of cancer cells with high levels of replication stress. In conclusion a detailed understanding of the role of E2F-dependent transcription in oncogene-induced replication stress provides novel therapeutic approaches that will translate into significant benefits for cancer patients and their families.