META-SURVEILLANCE · The molecular nexus coupling Cell Metabolism to Cell cycle and Genome Surveillance

Metabolic fluctuations and changes in DNA replication and cell cycle dynamics orchestrate early development and tumorigenesis. Of particular interest are reactive oxygen species (ROS), by-products of basal metabolic reactions, and major signaling molecules driving cell proliferation, differentiation, and cancer cell growth. However, despite their utmost importance in cell physiology, how ROS signals communicate to the cell cycle and genome safeguard mechanisms remains poorly explored. My postdoctoral work has illuminated this topic by discovering novel redox-sensitive mechanisms that directly couple metabolic nucleotide fluctuations and oxygen starvation to DNA replication dynamics. These findings revealed that ROS-signaling could operate as a prime and cell cycle checkpoint-independent surveillance for replicating genomes. Since profound alterations in metabolic pathways and redox state naturally entail embryonic growth, cell differentiation, and cancer transformation, in such scenarios, can metabolic cues in the form of ROS align cell cycle states and DNA replication? In this application, I propose to address this question by dissecting the mechanisms that align core cell cycle machinery and replisome dynamics to endogenous ROS fluctuation in tailor-made cellular models of early mammalian development (stem cells) and cancer. By combining innovative analytical tools, including CRISPR-based tagging of endogenous proteins with biochemistry and advanced cell biology (e.g., quantitative single-cell imaging of redox-state, Cyclin-CDKs, and genome caretakers; replication fork sequencing), I will define the molecular nexus coupling metabolism with genome surveillance at the global (genome-wide) and local (replisome) level. These investigations will provide an unmatched picture of regulatory foundations of cellular and genome integrity in normal and pathophysiological contexts, enhancing understanding of genome surveillance in development mechanisms and disease.