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. ADP-ribosyl transferase (ADPRT), also known as PARP-1, is a chromatin-associated enzyme that functions in DNA repair, transcriptional regulation, and controlled cell death. ADPRT initiates a DNA damage detection and repair pathway that corrects breaks in the structure of DNA, thereby functioning to maintain the integrity and stability of our genomes. Inhibitors of ADPRT sensitize cells to DNA-damaging agents used in cancer therapy;therefore ADPRT has emerged as a promising target for cancer treatment. The catalytic activity of ADPRT is dramatically stimulated by DNA strand breaks. Our objective is to structurally define the molecular mechanism of ADPRT activation. Understanding the mechanism of activation might reveal novel strategies for controlling ADPRT activity. We are currently focusing on a DNA-binding fragment of ADPRT in complex with DNA. The mode of DNA binding is currently unknown. Our data will be used to design structure-based mutants that test the function of this domain of ADPRT. Our long-term goals are to understand how ADPRT recognizes breaks in DNA structure, how DNA binding triggers ADPRT catalytic activity, and how ADPRT activation initiates DNA damage repair.
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