Tuberculosis (TB) remains a major public health threat, still emerging in many parts of the world. The burden of TB has been further exacerbated by the synergistic effect of HIV and consequently TB has become the most common cause of the death among HIV- infected adults in developing countries. Genome maintenance genes, comprised of replication, repair and recombination (3R) genes, are the main players in the adaptation and fitness for survival of Mycobacterium tuberculosis (Mtb) in the hostile environmen t inside host macrophages. The overall goal of this project is to elucidate the role of DNA repair genes in the pathogenesis of Mtb and to determine implications for novel therapeutics and preventive measures. We will search for the entire set of genes as sociated with Mtb DNA repair. To obtain insight in the role of putative DNA repair genes under in vitro and in vivo conditions, these genes will be genetically modified and expressed as recombinant proteins. Subsequently, the enzymatic activities of the p roteins encoded by these genes will be characterized. Studies of DNA repair in Mtb and the relationships to genome (in)stability and strain variation will lead to a better understanding of the entire DNA metabolism. This new understanding is a prerequisit e to combat the increasing occurrence of tuberculosis. In addition, the insights into the adaptation of Mtb that will be gained through this project should allow improved strategies for treatment and control and possibly reveal new targets for interventio n.