Metabolic regulation of mammalian DNA replication

DNA replication is essential for a cell to multiply and transfer genetic information to its daughters. However, various endogenous and exogenous threats challenge accurate DNA replication.

Such ‘Replication stress’, defined as perturbations that stall individual forks, is a key driver of genomic instability, fueling tumorigenesis and developmental disorders.

How DNA replication responds to endogenous threats, such as the metabolic rewiring characteristic of early development and tumorigenesis remains poorly understood.

Exploring the physiology of replication stress, I have recently discovered an unexpected coupling between metabolic activities and DNA replication (Somyajit et al., Science 2017, Dev Cell 2021; Sedlackova et al., Nature 2020) in cancer cell lines.

Since profound metabolic alterations are inevitable during early development and cancer, my findings raise the hitherto unrecognized and unanswered question of how DNA replication adapts to such metabolic changes.

Therefore, I propose to explore the coupling between gross metabolic alterations and DNA replication in various mammalian cell culture models of early development and tumorigenesis.

Using classical cell biology and genetics along with single-molecule and genome sequencing tools, I will systematically profile replication fork speed and define the mechanisms coupling metabolism and DNA replication. These experiments will help us understand the fundamentals regulating DNA replication in development and disease.