Overview
Supervisor: Hana Hanzlíková
Project description
ADP-ribosylation is a vital post-translational modification involved in DNA repair, chromatin remodelling, transcription regulation, and cell death. Despite advancements in understanding Poly-ADP-Ribose Polymerases (PARPs), particularly PARP1 and PARP2, their specific roles in these processes, especially in the brain, remain incompletely understood. Persistent or aberrant ADP-ribosylation, triggered by DNA damage or transcriptional stress, can disrupt neuronal function and transcriptional regulation, contributing to neurological disorders.
This project focuses on unravelling the molecular mechanisms of histone serine mono-ADP-ribosylation, with an emphasis on its regulation by PARP2 and its relevance to neurological diseases. We hypothesize that histone serine ADP-ribosylation modulates chromatin structure and gene expression—processes crucial for neuronal development, function, and responses to stress. Dysregulation of these mechanisms may promote neurodegeneration.
To address this, we utilize advanced experimental models, including patient-derived iPSCs, 3D cerebral organoids, and knockout mice, alongside state-of-the-art molecular tools such as CUT&RUN, mass spectrometry, single-cell RNA sequencing, and spatial transcriptomics. These approaches enable a comprehensive investigation of PARP2-driven histone ADP-ribosylation and its impact on brain-specific regulatory networks under normal and stressed conditions.
By providing new insights into how histone serine ADP-ribosylation influences chromatin dynamics and gene regulation in neurons, this research aims to uncover novel biomarkers and therapeutic strategies for neurological diseases.
Candidate profile
We are seeking a highly motivated candidate with a strong foundation in biochemistry, molecular biology, and cell biology. Applicants must hold a relevant Master’s degree and have a keen interest in our research area. Experience with advanced techniques such as mass spectrometry, single-cell RNA sequencing, or spatial transcriptomics is an advantage. The ideal candidate should demonstrate excellent teamwork skills and a collaborative mindset, as the position involves close interaction with other lab members and international partners. A proactive attitude and a willingness to engage with diverse experimental models and cutting-edge technologies are essential.
We provide an enthusiastic and inspiring research environment, supported by state-of-the-art facilities, at an attractive working location in Prague, Czech Republic. Our research is internationally recognized and driven by collaborative efforts. The lab works closely with leading research groups, including the Caldecott group at the University of Sussex, UK, and the Rottenberg and the Hanzlikova group at the University of Bern, Switzerland.
Suggested reading
Hrychova K, Burdova K, Polackova Z, Giamaki D, Valtorta B, Brazina J, Krejcikova K, Kuttichova B, Caldecott KW, Hanzlikova H: Dispensability of HPF1 for cellular removal of DNA single-strand breaks. Nucleic Acids Res 2024.
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.
Hoch NC & Hanzlikova H, Rulten SL, Tétreault M, Komulainen E, Ju L, Hornyak P, Zeng Z, Gittens W, Rey SA, Staras K, Mancini GM, McKinnon PJ, Wang ZQ, Wagner JD; Care4Rare Canada Consortium; Yoon G, Caldecott KW: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature 2017 541(7635):87-91.
APPLY AT: img.cas.cz/phd
