Secondary structures such as G-quadruplexes (G4s) can form within DNA or RNA. They pose a dramatic risk for genome instability, because due to their stability they can block DNA replication and this could lead to DNA breaks. In certain cancer cells mutations/deletions are observed at G4s, if a helicase that is important for G4 unwinding is mutated. Nevertheless, G4s are also discussed to be functional elements for cellular processes such as telomere protection, transcription, replication, and meiosis.

The Paeschke group uses a combination of genetic, molecular biological and genome-wide approaches to identify and characterize novel G-quadruplex (G4)-interacting proteins. Initial experiments are performed using yeast as a model organism and gained information will be transferred into human cells where results will be linked to human health. They have developed three novel screening techniques that enable us to identify novel G4 interacts. Candidate proteins are further validated in vitro as well as in vivo. 

Due to the connection of G4s and cancer the data obtained in the Paeschke lab will not only be important to understand G4 regulation  and formation, but will also provide unique  knowledge on the impact of G4 structures for genome stability and thereby for human health.

Background:

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G4s are stable structures that can form in guanine-rich regions of RNA and DNA with specific sequence motifs. Although G4 structures were already discovered 1962 only recently a lot of attention was drawn to the biological function and challenges of G4 structures in vivo. Research in the Paeschke lab has contributed significantly to the in vivo understanding of G4 structures and revealed how G4s affect telomere maintenance, DNA replication, and genome stability.

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​As G4 motif requirements for G4 structure formation are known, it was possible to identify the locations of G4 motifs in whole genomes using computational tools. They are enriched at specific regions such as telomeres, promoters, mitotic and meiotic double strand break (DSB) sites, and origins of replication (1-3). Accordingly, G4 structures could be involved in telomere maintenance, (post-)transcriptional regulation, or meiotic DSB formation (Figure 1a-e). To date, it is not known if G4 structures are relevant for one or several of these biological processes. Furthermore, the specific function of identified G4 structures in these processes is still not understood. The current model is that it is unlikely that all G4s will have the same function in the cell. It is postulated that specific G4 structures form upon certain “trigger events”, such as transcription or meiosis, and some only under certain conditions, such as stress. In the current model, G4 structures are key regulatory elements that are essential for the correct and efficient execution of certain processes. ​

Research Projects:

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• Uncover the role of G4 structures for double strand break formation
• Reveal the function and regulation of G4 structures during Nucleotide Excision Repair (NER)
  
• Identify and characterize novel G4 interacting proteins and their biological function
• Analyze the impact of DNA and RNA helicases and G4 formation in vivo
• Determine telomerase function within the genome
• Uncovering how G4 structures impact cancer development and tumorigenesis