3 OVERALL PROGRAM CRITIQUE 3 PROGRESS DURING THE CURRENT FUNDING PERIOD 4 PROGRAM LEADERSHIP 4 PROGRAM AS AN INTEGRATED EFFORT 5 COLLABORATING INSTITUTIONS 8 BUDGETARY OVERLAP 8 ADDITIONAL REVIEW CRITERIA: 8 ADDITIONAL REVIEW CONSIDERATIONS: 8 PROJECT 1: Cellular Responses to Interstrand Cross-Links in S Phase: Replication Fork Collapse, Checkpoint Activation, and Repair Complex Assembly (Randy J. Legerski, PhD) 9 PROJECT 2: Recognition and Processing of Complex Lesions by Components from Multiple DNA Repair and Recombination Pathways (Karen M. Vasquez, PhD) 17 PROJECT 3: Functional Links between Fanconi Anemia Proteins and Interstrand Crosslinks (Lei Li, PhD) 26 PROJECT 4: Mechanisms of DNA Interstrand Crosslink Unhooking and Translesion Synthesis (Richard D. Wood, PhD) 35 CORE A: Administrative Core (Randy J. Legerski, PhD) 1 CORE B: Mammalian Cell Resource Core (Rodney S. Nairn, PhD) 3 CORE C: Protein Purification and DNA Substrates Core (Lei Li, PhD) 5 COMMITTEE BUDGET RECOMMENDATIONS 9 SPECIAL EMPHASIS PANEL ROSTER DESCRIPTION (provided by applicant): The mechanisms by which complex lesions, particularly interstrand cross-links (ICLs), are removed or repaired in mammalian cells are poorly understood despite the importance to human health of compounds that induce these lesions. These agents, present in foodstuffs and produced as byproducts of mammalian metabolism, are highly toxic and mutagenic. Conversely, some of these drugs are also employed as highly active anti-tumor agents. The long term objectives of this application, involving four highly integrated projects and three cores, aim to elucidate the molecular mechanisms of repair of ICLs with the anticipation that the knowledge gained from these studies will be of significant value to understanding both the etiology of tumorigenesis and the enhancement of chemotherapeutic regimens. This proposed dissection of the mechanisms of ICL repair will encompass both mutagenic and non-mutagenic pathways, as well as the complete process of repair from lesion recognition to the final stages of restoration of helical integrity. Biochemical, molecular, and genetic approaches will be employed to elucidate of [sic] the mechanistic details of the multiple pathways of ICL repair. In addition, another objective of this application is to explore potential uses of ICL inducing compounds as a methodology to enhance recombination and mutagenesis in mammalian cells. Specifically, the use of triplex technology will be employed to direct ICLs to a particular genetic target. These approaches have excellent potential to yield useful technical and therapeutic advances in genetic manipulation.
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