DNA replication is a crucial, but potentially dangerous process in every cellular division. A failure to maintain the integrity of replicating chromosomes leads to genome instability, an early event in tumorigenesis. Most common anti-cancer drugs also interfere with DNA synthesis, by largely undefined mechanisms. My lab specializes in the structural and molecular characterization of DNA replication stress in higher eukaryotes, combining standard cell and molecular biology with specialized single molecule analysis of replication intermediates.
The first aim of our research is to gain mechanistic information about the elusive impact of oncogene activation on DNA replication. By direct structural analysis of tissue culture models of tumorigenesis, we have recently uncovered specific defects in DNA synthesis associated with DNA damage checkpoint activation. We plan to expand these studies to compare the effect of different oncogenes and to identify cellular factors modulating oncogene-induced genotoxicity.
We are also elucidating the cytotoxic mechanisms of anti-cancer drugs that challenge DNA replication. Comparing the molecular consequences of chemotherapeutic treatments in control cells and cells lacking cancer-related factors, we plan to uncover how precisely different drugs interfere with replication and which cellular players mediate their cytotoxicity. We plan to complement these studies with a proteomic-based screen, to identify novel factors modulating replication of a damaged template.
Finally, we plan to analyze replication features in different populations of stem cells, as the cellular response to replication stress was recently proven essential for stem cell maintenance. We aim to provide mechanistic insight into the constitutive activation of the DNA damage response reported in embryonic stem cells. We also plan to expand these investigations to hematopoietic stem cells, where we recently observed similar phenomena upon stimuli-induced proliferation.
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