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Research

Cell cycle, checkpoint, protein phosphorylation, oncogenic transformation

Proliferation of cells is essential for keeping organisms alive and healthy and is accomplished by passing through interphase followed by nuclear division (mitosis) and cellular division (cytokinesis). In response to DNA damage, cells temporarily stop progression through the cell cycle (checkpoint) to prevent transmission of mutations to progeny. After completion of DNA repair, cells are allowed to reenter the cell cycle (checkpoint recovery). Cells that are exposed to a massive genotoxic stress that exceeds the capacity of DNA repair are eliminated by programmed cell death. Radiotherapy and chemotherapy with genotoxic pharmaceuticals represent two commonly used non-surgical strategies in treatment of human tumours and they both rely on induction of cell death by genotoxic stress. Progression through the cell cycle and cellular responses to DNA damage are tightly controlled by interconnected signalling cascades. Malfunction of cellular checkpoints causes accumulation of mutations and can lead to genome instability, activation of oncogenes and eventually to malignant transformation.

In our laboratory we employ cell biology, CRISPR-mediated gene editting, molecular biology and biochemical approaches to identify molecular mechanisms that control cellular responses to DNA damage. In particular we focus on protein phosphatase PPM1D/Wip1 that plays an essential role in switching off the DNA damage response pathway, termination of the checkpoint and control of checkpoint recovery. PPM1D/Wip1 is an important negative regulator of the tumour suppressor p53. Recent data from transgenic mice and from human tumours implicate PPM1D/Wip1 as oncogene. Our work aims to decipher molecular mechanisms regulating the function of PPM1D/Wip1 in human cells and in mouse models. In addition, we use chemical genetics to evaluate PPM1D/Wip1 as a potential pharmacological target.

Highly motivated graduate or master students can send application inquiries (including CV and contact information on 2 referees) to Libor Macurek (libor.macurek@img.cas.cz).

Fig. 1.Cells were exposed to ionizing radiation and stained for markers of DNA damage. Nuclear foci positive for gH2AX and 53BP1 are present in interphase cells, whereas mitotic cell fail to form 53BP1 foci. For detaild explanation see Benada et al. Cell Cycle, 2015.
Fig. 2. Schematic representation of WIP1 phosphatase function in termination of the DNA damage response. For details see Medema and Macurek, Oncogene 2012
Fig. 3. Healthy cells do not divide in the presence of DNA damage and arrest in G1 phase of the cell cycle (red). Cells carrying mutation in PPM1D gene continue progression through the cell cycle also in the presence of DNA damage and start replicating their genome (orange). Mutation in PPM1D does not affect cells in the G2 phase of the cell cycle. Photograph Indra A. Shaltiel (NKI) and Libor Macůrek (IMG AS CR). For details see Kleiblova et al., JCB 2013.

 

 

Presentation

General mechanisms of the normal cell cycle progression and activation of the DNA damage-induced checkpoint arrest. Possible role of Wip1 oncogene expressed at abnormally high levels in oncogenesis. For detailed description see Kleiblova et al., JCB 2013. Figure3 Wip1 mechanism ENG - ppt

 

Video

The role of Wip1 in tumor WP1_role  

Last change: February 26, 2016