Project description
Insight into DNA replication for cancer prevention
DNA replication – the process of copying the genetic information prior to cell division – is central for maintaining genomic integrity in progeny cells. DNA replication involves a complex of proteins, the pre-replicative complex (pre-RCs), that regulate the initiation of DNA replication and prevent DNA damage. The EU-funded HS_MSCA_2021 project aims to identify the mechanisms regulating pre-RC formation and their role in genetic instability during normal mammalian development and oncogenic cellular transformation. Researchers will study how the regulation of pre-RCs may lead to genome instability and determine the signalling pathways responsible for optimal pre-RC levels. Project findings could lead to the identification of new anticancer drug targets, paving the way towards more effective cancer treatments.
Objective
The development of the human body starts from a single cell, fertilized egg, which divides about ten trillion times to form an adult human. During every cell division, the genome is duplicated with great accuracy by DNA replication and distributed with one copy to each of the two daughter cells. Understanding how the cell regulates DNA replication remains one of the most fundamental questions in biomedicine, because up to two-thirds of all cancers are caused by accumulation of errors during DNA replication. Pre-replicative complexes (pre-RCs) serve as essential precursors for DNA replication and their accurate levels are critical to alleviate genome instability associated with severe diseases, including cancer. Indeed, the overexpression of pre-RCs has been reported at early stages of variety of cancers making them an attractive target for cancer therapy. On the other hand, programmed genetic instability is part of the normal mammalian development, including heart cells. The aim of this project is to map differences in the mechanisms that regulate pathological and physiological genetic instability, an area that remains largely unexplored. We will identify signaling pathways responsible for optimal levels of pre-RCs and understand their contribution to genome instability during oncogene-induced tumorigenesis and programmed polyploidy during cardiomyocytes maturation in normal mammalian development. By combining physiologically relevant mammalian cellular models with state-of-the-art CRISPR-Cas9 genome editing, quantitative cell biology, genomics, and proteomics approaches we will address mechanism regulating accurate pre-RC formation and its role in physiological and oncogenic cellular transformation. Our findings will lay the foundations for the development of new anticancer drug targets and thereby expand therapeutic strategies for treatment of cancer associated with misregulated pre-RC levels and poor prognosis.
Fields of science
Programme(s)
Funding Scheme
MSCA-PF - MSCA-PFCoordinator
CZ-61265 Brno
Czechia