PhD position / project: Defective DNA damage responses and RNA processing in human disease

Genome Dynamics

The main research of our group is focused on ADP-ribosyl transferases; a class of DNA repair enzymes that detect DNA single-strand breaks (SSBs) and signal their presence by catalysing the rapid synthesis of mono(ADP-ribose) and poly(ADP-ribose) and hydrolases; enzymes that catalyse the removal of specific ADP-ribosyl modifications from proteins… More about the laboratory

Project: Defective DNA damage responses and RNA processing in human disease
Supervisor

Hana Hanzlíková

Project description

Defects in DNA break repair, as well as alterations in RNA metabolism, are frequently associated with neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of these processes in long-lived postmitotic neurons. We investigate the molecular mechanisms by which DNA breaks are detected and repaired, and we are especially interested in identification and characterization of protein factors and pathways that couple aberrant DNA repair and RNA metabolism to human neurodegenerative disease. Based on our recent exciting data (see below) we propose that the impact of aberrant DNA strand break repair and/or RNA processing on neurodegeneration extends beyond rare DNA repair-defective diseases to more common neurodegenerative diseases including dementia, and are possibly also an etiological factor in normal human ageing.

In the scope of this PhD position, we intend to address this hypothesis and identify new mechanisms which trigger neurodegeneration. We will develop a variety of advanced biochemical, proteomic and genetic approaches to understand the effects of defective DNA repair and unprocessed RNA on neurodegeneration. We will use various model systems, including human iPSCs, 2D neuronal cell lines and 3D organoids as well as genetically engineered mouse models.

Candidate profile

We are looking for a highly motivated candidate with a solid background in biochemistry, molecular biology and cell biology. Applicants must have a relevant Master’s degree and preferably expertise in DNA damage responses, RNA biology, iPSC culture and/or mice handling, or at least must be enthusiastic and willing to work with a mouse model. The candidate should be a team-player and willing to work with other lab members and international collaborators.

We offer an enthusiastic, young, inspiring research environment and state-of-the art research facilities at an attractive working location in Prague, Czech Republic. We closely collaborate with the Caldecott group at the University of Sussex in the UK and the Rottenberg group and the Hanzlikova group at the University of Bern in Switzerland, so there will be an opportunity for a period of research spent abroad.

Suggested reading

  • Cihlarova Z, Kubovciak J, Sobol M, Krejcikova K, Sachova J, Kolar M, Stanek D, Barinka C, Yoon G, Caldecott KW, Hanzlikova H: BRAT1 links Integrator and defective RNA processing with neurodegeneration. Nat Commun 2022 13(1): 5026. [pubmed] [doi]
  • Wu W, Hill SE, Nathan WJ, Paiano J, Callen E, Wang D, Shinoda K, van Wietmarschen N, Colón-Mercado JM, Zong D, De Pace R, Shih HY, Coon S, Parsadanian M, Pavani R, Hanzlikova H, Park S, Jung SK, McHugh PJ, Canela A, Chen C, Casellas R, Caldecott KW, Ward ME, Nussenzweig A: Neuronal enhancers are hotspots for DNA single-strand break repair. Nature 2021 593(7859): 440-444. [pubmed] [doi]
  • Hanzlikova H, Prokhorova E, Krejcikova K, Cihlarova Z, Kalasova I, Kubovciak J, Sachova J, Hailstone R, Brazina J, Ghosh S, Cirak S, Gleeson JG, Ahel I, Caldecott KW: Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair. Nat Commun 2020 11(1): 3391. [pubmed] [doi]
  • Kalasova I, Hailstone R, Bublitz J, Bogantes J, Hofmann W, Leal A, Hanzlikova H, Caldecott KW: Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair. Nucleic Acids Res 2020 48(12): 6672-6684. [pubmed] [doi]

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