Regulation of DNA replication during normal development and tumorigenesis
ABSTRACT:
The development of the human body begins with a single cell of a fertilized egg, which must accurately replicate the entire DNA material and divide it between two daughter cells. These fundamental cellular processes, DNA replication, and cell division are constantly repeated until the generation of ten trillion cells that form the human adult body. How the cell regulates DNA replication to achieve ultra-high accuracy in genome duplication remains one of the fundamental questions in biomedicine in general because up to two-thirds of all cancers are believed to arise due to the accumulation of errors during genome duplication. Cancer research has made great progress in identifying and developing numerous chemotherapeutic drugs targeting DNA replication in recent years. One of the emerging attractive anticancer targets is the pathway regulating assembly of pre-replicative complexes (pre-RCs), which serve as essential precursors for replication forks (basic units of DNA replication) and their accurate levels are critical to alleviating genome instability. In fact, overexpression of pre-RCs has been reported at early stages of tumorigenesis in a variety of premalignant dysplasia and cancers and is associated with poor prognosis. On the other hand, genetic instability advancing nuclear polyploidy and tumor development is also part of the normal mammalian development of specialized tissues, such as heart cells (cardiomyocytes). Strikingly, adult cardiomyocytes showing high levels of nuclear polyploidy undergo very rarely malignant transformation. However, what are the differences in mechanism(s) regulating physiological and pathological nuclear polyploidy frequently observed during malignant transformation and in early development remain largely unexplored. Therefore, we aim to decipher the signaling network controlling the dynamic equilibrium of pre-RCs and understand its contribution to genetic instability during oncogene-induced malignant transformation and programmed polyploidy specifically during cardiomyocyte development (cardiomyogenesis). The main expected scientific impact of the project is to bring new fundamental discoveries in regulatory foundations of mammalian DNA replication in physiologically relevant cellular models of oncogene-induced malignant transformation and cardiomyocytes. The discoveries made in this project are likely to decipher new biological mechanisms ensuring error-free DNA replication critical to prevent genome instability with both cancer development and heart muscle development. In addition, the newly identified mechanisms may reveal new drug targets and therapeutic strategies for myocardial diseases and therapeutic strategies for the treatment of cancer associated with imbalanced pre-RC levels and poor prognosis.
ERA FELLOW: Dr. Hana Polasek-Sedlackova
DELIVERABLES:
Communication, Dissemination & Outreach Plan
This project has received funding from the European Union’s Horizon 2022 Widera Talent program under ERA grant agreement 101090292.
