“The dream of every cell is to become two cells” - François Jacob
Central to the propagation of life is the faithful duplication of genetic material. Given the fundamental importance of DNA, the fact that this molecule itself could be unstable, and prone to damage or alteration was not fully considered, despite evidences of mutagenesis from radiobiological studies from the 1920s. Errol C. Friedberg writes in the ‘historical account of the discovery of DNA repair mechanisms’ about his conversation with Franklin Stahl, who said, “…the possibility that the genes were dynamically stable, subject to the hurly-burly of both insult and clumsy (i.e., enzymatic) efforts to reverse the insults, was unthinkable.”
Decades of seminal work has now established that DNA damage is a prevalent threat to genome integrity, and cells across domains of life have evolved dedicated and conserved pathways for repairing or tolerating the same. While DNA repair is important for the faithful propagation of life, pathways of repair can also be sources for mutagenesis. Apart from their impact on evolution, such inducible mutagenesis can lead to genetic defects and cancer in human cells as well as antibiotic and stress resistance in bacteria. Thus, the modulation of these pathways can have significant impact on cellular adaptation and survival. This becomes particularly relevant in organisms such as microbes, that live in constantly fluctuating environments.
The overall objective of our work is to understand the fundamental regulatory mechanisms that govern the activity of genomic error-correction pathways, and how this can drive genome evolution under genotoxic stress. We primarily use imaging approaches, in combination with other interdisciplinary tools, to understand how DNA damage response and repair is regulated in microbial systems. Presently, we have focused our efforts on understanding how specific steps of response and repair are regulated in vivo, under the following themes:
To change or not to change: regulation of mutagenic and non-mutagenic mechanisms of DNA repair
2. Co-evolution of genomes and their error-correction mechanisms
See Spotlight for a summary of some ongoing projects!