Grant: Project Grant

Cells originate from other cells. A crucial part of this process requires them to inherit their DNA to the next generation. This task is accomplished by an elegant multicomponent protein machine, called the replisome. Even though the basic underlying chemical reactions are understood, the question of how this machine works remains unanswered. Since the initial description of the replisome in bacteria, it was thought that a tight physical association among its components allowed them to act as a single unit. As such, the replisome could function uninterrupted from the time it starts copying the long chromosomal DNA, to the point it finishes it, one hour later! Making an analogy, it would be like typing at a rate of 1,000 letters per second for an hour-period without making any mistakes. Not to mention that mistakes, prolonged pauses, or the permanent inability of the writer to continue, can cause complete loss of the text - and for the cell, its death. Recent data from my lab shows instead that most replisome components participate in the process in pulses that last for few seconds - in the analogy, a new writer would seat in front of the keyboard every few hundreds of words. As this discovery was unexpected in the field, its molecular causes and consequences for the cell are yet unknown. Understanding these aspects is the aim of this proposal. As DNA replication in bacteria is a factor in the spread of antibiotic resistance and a potential target for antibiotics, the outcome of our work may help in the development of new strategies to counter the current antibiotic resistance crisis.