Project description
Biomolecular condensates as spatial organisers of DNA replication
In simple organisms, DNA replication relies on non-coding sequences denoting where replication begins. In humans, replication initiation is vastly more complex, involving epigenetic factors, including unusual DNA structures called G-quadruplexes (G4s). RECQ4, a DNA helicase, binds tightly to G4s. However, a potential role of RECQ4 in transcription activation is confounded by evidence that RECQ4’s dysregulation may lead to unchecked replication rather than impeded replication. Specifically, RECQ4 mutations cause cancer predisposition and overexpression drives aggressive cancers. With the support of the Marie Skłodowska-Curie Actions programme, the ReG4CoRe project aims to resolve these contradictions. It will investigate whether RECQ4 and G4 form biomolecular condensates, whether these organise replication origins, and how they are regulated.
Objective
DNA replication is the core process that ensures faithful duplication of the genome in every cell of every organism. While the replication process is well-characterised in simple organisms, the regulation becomes increasingly complex in higher eukaryotes, such as humans. The human genome lacks consensus origin-defining sequences and is demarcated via a mix of epigenetic factors, including non-canonical DNA structures. Among these, G-quadruplexes (G4s) act as functional origin motifs via their co-occurrence with the origin G-rich repeated elements. Interestingly, the origin recognition complex (ORC) and RECQ4 possess high affinity to G4s. While ORC's role in origin licensing is well established, RECQ4's function remains unresolved. RECQ4, a multifunctional helicase, is involved in replication and DNA repair. However, its relevance in origin firing remains controversial as studies categorise it as essential or redundant. RECQ4 mutations are associated with three recessive disorders causing cancer predisposition. Contrastingly, the gene is overexpressed in various aggressive cancers, including breast cancer and prostate cancer. These studies belie the biological and clinical significance of RECQ4. Given that unchecked replication potential is a hallmark of cancer, RECQ4's function in replication, when altered, may induce carcinogenesis. Interestingly, recent studies also suggest that RECQ4's role in replication may be context-dependent and associated with its phosphorylation status. Further, studies from the host lab have demonstrated that RECQ4 interacts with G4 with high affinity, leading to biomolecular condensation in vitro. This project aims to link these findings and reconcile the controversies regarding RECQ4's function. We propose that RECQ4-G4 condensates likely act as spatial organisers of replication origins, regulated by protein-protein/protein-nucleic acid interactions and post-translational modifications.
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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(opens in new window) HORIZON-MSCA-2025-PF
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601 77 Brno
Czechia
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