Mechanical Dissection of DNA repair enzymes

• Applicant: Dr. Andrés Manuel Vera Gómez
• Subject Area: Biophysics ; Biochemistry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 522200875

The genome of all living organisms, including humans, are continuously being damaged by external agents, such as UV light, and by cellular processes. If not repaired, these damages can lead to cellular malfunction and death, mutations and eventually cancer and ageing. Therefore, these damages must be swiftly repaired to ensure survival and genome stability. Cells have developed several DNA repair mechanisms targeting different types of DNA damage. Among them, the BER (base excision repair) system repairs the most common type of lesion, namely DNA base damage. The initiators of the BER pathways are enzymes detecting the damage and producing a severe bending of the DNA before cutting one of the DNA strands to start the repair process. Understandingly, mechanical tension in the DNA opposes DNA bending and affects the mechanical deformation of the DNA. Although active genomes are under mechanical strain produced by physiological cellular processes, their effect on the activity of BER enzymes is not understood. In this proposal, we aim to apply recently developed technological advances to study how forces affect the activity of BER enzymes with unprecedented detail and ultimately unveil the role of mechanical stress in the repair of DNA. Using a combination of DNA nanotechnology and single-molecule fluorescence approaches, we will apply tension to DNA molecules and observe the inner working of BER enzymes in order to elucidate how forces affect their activity. Improving our understanding of the mechanical regulation of DNA repair is not only of fundamental biological interest, it is essential to face current societal challenges. The impairment in DNA repair is closely related to aging and aging-related diseases, such as neurodegenerative diseases and cancer. In fact, DNA damage affects most aspect of ageing, making it a unifying cause of ageing. Furthermore, DNA damage has been recognized as causal factor for cancer development, and provides an important avenue for therapies. With the progressive ageing of the world population, an integral understanding of DNA repair mechanisms, including their mechanoregulation, will become more and more important to develop effective strategies for healthy ageing and to devise new drugs targeting this mechanoregulation.

• DFG Programme: Research Grants