This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal of this work is a structure-based understanding of 1) replication initiation and 2) nucleotide excision repair (NER). Replication initiates at multiple sites on the genome called origins of DNA replication. Specialized protein complexes bind at these sites and prepare the duplex for replication. The activity of these ensembles is tightly controlled to ensure that only one copy of the genome is made per cell cycle. The architecture, regulation and mechanisms of action of these large complexes are incompletely understood. Our work is of practical significance because regulatory changes in origin complexes contribute to human cancers. Efforts with bacterial complexes will provide much needed targets for development of novel antibiotics. The first steps in NER are performed by three proteins: UvrA, UvrB and UvrC. The UvrA+UvrB ensemble monitors DNA and recognizes damage. On encountering damage, UvrA exits the complex, leaving UvrB stably bound at or near the lesion site. Damage searching, formation of the DNA complex and dissociation of UvrA are regulated by ATP. UvrB then recruits the endonuclease UvrC, which catalyzes incisions on either side of the lesion. Additional processing reactions lead to restoration of the original DNA sequence.
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