PhD position / project: Function of PPM1D phosphatase in control of genome integrity in human cells

Cancer Cell Biology

In our laboratory, we employ cell and molecular biology approaches, CRISPR-mediated gene editing and transgenic mouse models to investigate how cells respond to DNA damage. We also seek for genetic defects in cancer cells that could be exploited for personalized cancer treatment… More about the laboratory

Project: Function of PPM1D phosphatase in control of genome integrity in human cells

Supervisor

Libor Macůrek

Project description

Genome instability is one of the main drivers of cancer. Integrity of the genome is protected by a temporal arrest of the cell cycle in the presence of DNA damage and by efficient DNA repair. Tumor suppressor p53 and its downstream target p21 are efficient inducers of the cell cycle checkpoint. Inversely, protein phosphatase PPM1D is a negative regulator of p53/p21 pathway and allows renewal of the proliferation after DNA repair. Defects in p53 pathway or overexpression of PPM1D promote tumorigenesis by silencing the cell cycle checkpoint. This project aims to elucidate new molecular mechanisms of PPM1D function besides its established role in checkpoint recovery. We have recently identified that a fraction of PPM1D localizes at human telomeres and controls phosphorylation of the shelterin complex.

We will investigate how PPM1D activity affects DNA replication and DNA repair at telomeres. To this end we will use CRISPR/Cas9 technique to induce damage of the telomeric DNA and recruitment of DNA repair factors will be followed by quantitative microscopy. Molecular biology and biochemistry will be used to map the regions involved in PPM1D function at telomeres and for control of its protein stability. Overall, the project will contribute to understanding of PPM1D function in control of genome integrity.

Candidate profile

The laboratory of Cancer Cell Biology seeks for a motivated a curious PhD student with deep interest in basic mechanisms of cell function. The candidate should hold degree in cell/molecular biology or biochemistry. The candidate should be able to efficiently work in the team and communicate in English. Previous hands-on experience with cell biology, telomere biology or DNA repair techniques is considered advantage but is not required.

Suggested reading

  • Storchova R, Palek M, Palkova N, Veverka P, Brom T, Hofr C, Macurek L. Phosphorylation of TRF2 promotes its interaction with TIN2 and regulates DNA damage response at telomeres. Nucleic Acids Research (in press)
  • Burocziova M, Burdova K, Martinikova AS, Kasparek P, Kleiblova P, Danielsen SA, Borecka M, Jenikova G, Janečková L, Pavel J, Zemankova P, Schneiderova M, Schwarzova L, Ticha I, Sun XF, Jiraskova K, Liska V, Vodickova L, Vodicka P, Sedlacek R, Kleibl Z, Lothe RA, Korinek V, Macurek L. Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon. Cell Death Dis. 2019; 10:818. [pubmed] [doi]
  • Jaiswal H, Benada J, Müllers E, Akopyan K, Burdova K, Koolmeister T, Helleday T, Medema RH, Macurek L, Lindqvist A. ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration. EMBO J. 2017; 36:2161-2176. [pubmed] [doi]
  • Kleiblova P, Shaltiel IA, Benada J, Ševčík J, Pecháčková S, Pohlreich P, Voest EE, Dundr P, Bartek J, Kleibl Z, Medema RH, Macurek L. Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint. J Cell Biol. 2013; 201:511-21. [pubmed] [doi]

Application: https://www.img.cas.cz/career/phd-programme/application/