Molecular and cellular mechanisms utilized by Primase-Polymerase centric DNA repair pathways during stationary phase in mycobacteria

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Our cells DNA, the so called "genetic blueprint of life", encodes the information for all our genes. DNA has a simple repeating structure composed of two complementary strands of DNA composed of bases, which form long, string-like, double-helical structures that make up the genome. Our genome is packaged away into chromosomes, contained within the nucleus of nearly every cell. This information must be faithfully copied as cells divide to produce daughter cells. Cells produce a large number of proteins responsible for "photocopying" this DNA blueprint. The proteins tasked with accurately copying the several billion letters of our genetic code are called DNA polymerases. During this copying process, the replication machinery can introduce mutations to the newly made DNA sequence that can, if left unrepaired, lead to the development of disease states, such as cancer. The integrity of DNA is also constantly being challenged by various damaging agents. These agents include high energy UV and X-ray radiation from the sun, chemicals - both man-made and environmental - and even the oxygen we breathe can damage DNA. Fortunately, our cells produce repair proteins whose role it is to remove the "damaged" bases. We have recently discovered a novel bacterial DNA repair "machine" that plays an important role in excising and repairing these "toxic" mutations thus ensuring genome stability and, ultimately, cell survival. In this research programme, we are proposing to determine how these repair machines detect, remove and correct DNA mutations, define the cellular consequences of deleting this repair pathway and, finally, determine if it co-operates with other related repair pathways to ensure genome stability. This proposal will provide critical insights into a fundamental DNA repair pathway required to correct harmful genetic mutations that promote genetic instability in bacterial pathogens.Excessive accumulation of damage can lead to uncontrolled cell growth that can result in the onset of diseases, such as cancer. However, in bacteria it can lead to the development of antibiotic resistance in major pathogenic bacteria. The rise of antibiotic resistance has been identified as one of the major threats facing global health. Therefore, understanding fundamental mechanisms and pathways that influence mutation rates in bacteria will uncover new strategies to predict and combat the development of antibiotic resistance.