The work in the lab focuses on two
main lines of investigation.
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.
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
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
Cell cycle regulated transcription and control of
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.
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
Yeast as a model for human cells,
human cells as a model for cancer.
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
The role of E2F activity in
oncogene-induced replication stress.
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
novel therapeutic approaches that will translate into significant benefits for
cancer patients and their families.