Forschung

Research Profile

DNA damage is a well-recognised causal factor of gene dysfunction in cancers and age-related diseases. Exposed to reactive endogenous metabolites and environmental toxicants, DNA of all living cells continuously suffers chemical alterations. Dozens of structurally different modifications ("DNA lesions") have been identified to date; however, repair and other responses to DNA damage have been satisfactorily characterised for just a few. Our group specialises in the assessment of repair and functional consequences of structurally defined DNA lesions.

We exploit synthetic nucleotide derivatives that exactly correspond to biologically highly relevant DNA modifications induced by food carcinogens, drugs, environmental toxicants and endogenous cellular mechanisms. We have developed procedure for efficient incorporation of such synthetic DNA lesions into functional reporter gene elements. To understand the lesion-specific repair mechanisms and harmful consequences of individual lesions, we deliver these gene constructs to host cells in which defined components of DNA repair or DNA damage response pathways are impaired by pre-existing genetic defects (cells derived from patients) or have been artificially compromised (by genetic tools or inhibitors). On the long run, the knowledge of molecular and cellular mechanisms underlying the outcomes of lesion-specific responses to DNA damage shall help to characterise hazards of exposure to specific genotoxic agents and identify molecular susceptibility markers as well as potential targets for personalised therapeutic interventions (for instance, cytotoxic treatments of tumours). Current projects follow three major directions

• Fundamental mechanisms of DNA repair - nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR)
• Epigenetic and regulatory functions of DNA base modifications - dynamics of DNA modifications and transcriptional responses in the context of functional gene promoters.
• DNA damage as causal factor of disease - roles of DNA adducts arising from exogenous genotoxic exposures (environment, lifestile, diet, medications) in the aetiology of human diseases associated with hereditary DNA repair defects (Xeroderma pigmentosum, Cockayne syndrome and several other neurological and degenerative diseases)