MAIN RESEARCH PROJECTS:
1. Molecular mechanisms and characterization of ”G2 checkpoint adaptation”
When exposed to ionizing radiation, human cells activate cell cycle checkpoints to halt cell cycle progression until the DNA damage is repaired. When repair of the DNA damage is completed, cell cycle progression can resume. However, data from S.cerevisiae and Xenopus have suggested that there may be an alternative route to re-entering cell cycle progression before the damage is fully repaired, namely through a process termed ”Checkpoint adaptation”. As cell division in the presence of DNA breaks may increase the risk for genomic instability, checkpoint adaptation was long considered unlikely in human cells. However, we recently showed that human osteosarcoma U2OS cells entered mitosis following the IR-induced G2 checkpoint in the presence of γH2AX foci, a marker for DNA breaks. In our current project we are further characterizing this process and exploring the molecular mechanisms involved.
2. Inhibition of checkpoint kinases to modulate tumor radiosensitivity
An optimized cancer treatment should selectively affect cancer cells in order to spare the surrounding normal tissues. We want to explore whether abrogation of DNA damage signaling responses may be a valuable strategy for sensitizing tumors to radiation (or chemotherapeutic agents). In our current project we are testing the hypothesis that inhibition of Checkpoint kinase 1 (Chk1) may selectively affect hypoxic cancer cells, as well as cancer cells lacking the p53-dependent G1 checkpoint.
3. Large scale genetic screening to identify new regulators of checkpoint signaling
New powerful techniques for functional genetic screening have recently developed, based on RNA-interference. In the current project we are utilizing such siRNA-based large scale screens to search for unknown regulators of IR-induced checkpoints, in collaboration with Claus Sørensen´s group at BRIC Biocenter in Copenhagen. Essential for the siRNA screening is a fully equipped automatic robot workstation available at BRIC for rapid handling and imaging of large scale experiments.
When exposed to ionizing radiation, human cells activate cell cycle checkpoints to halt cell cycle progression until the DNA damage is repaired. When repair of the DNA damage is completed, cell cycle progression can resume. However, data from S.cerevisiae and Xenopus have suggested that there may be an alternative route to re-entering cell cycle progression before the damage is fully repaired, namely through a process termed ”Checkpoint adaptation”. As cell division in the presence of DNA breaks may increase the risk for genomic instability, checkpoint adaptation was long considered unlikely in human cells. However, we recently showed that human osteosarcoma U2OS cells entered mitosis following the IR-induced G2 checkpoint in the presence of γH2AX foci, a marker for DNA breaks. In our current project we are further characterizing this process and exploring the molecular mechanisms involved.
2. Inhibition of checkpoint kinases to modulate tumor radiosensitivity
An optimized cancer treatment should selectively affect cancer cells in order to spare the surrounding normal tissues. We want to explore whether abrogation of DNA damage signaling responses may be a valuable strategy for sensitizing tumors to radiation (or chemotherapeutic agents). In our current project we are testing the hypothesis that inhibition of Checkpoint kinase 1 (Chk1) may selectively affect hypoxic cancer cells, as well as cancer cells lacking the p53-dependent G1 checkpoint.
3. Large scale genetic screening to identify new regulators of checkpoint signaling
New powerful techniques for functional genetic screening have recently developed, based on RNA-interference. In the current project we are utilizing such siRNA-based large scale screens to search for unknown regulators of IR-induced checkpoints, in collaboration with Claus Sørensen´s group at BRIC Biocenter in Copenhagen. Essential for the siRNA screening is a fully equipped automatic robot workstation available at BRIC for rapid handling and imaging of large scale experiments.
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