The SCB Core will provide to all six SBDR Projects the following: 1) Macromolecular Crystallography and Small Angle X-ray Scattering data collection at the SIBYLS beamline located at beamline 12.3.1 of the Advanced Light Source synchrotron at LBNL. The SIBYLS beamline is a unique synchrotron resource that provides tunable wavelength X-rays for both MX and SAXS experiments. 2) Collaboration on SBDR targets with SCB staff for both MX and SAXS studies. 3) Development and application of SAXS analysis software to address current limitations and beamline hardware to optimize data quality for SBDR targets. This includes software that will combine results from high and low resolution techniques through the systematic and objective fitting of X-ray crystal structures that are consistent with the experimental SAXS data. 4) Analysis by Multi-angle Light Scattering (MALS) System in line with Size Exclusion Chromatography (SEC) in the SIBYLS wet lab. MALS with its 1% molecular mass accuracy is critical for validating complexes for SAXS analysis. 5) In silico and in vitro screening services to identify small molecule inhibitors for selected SBDR targets that control biological outcome and coordination of inhibitor studies with Joe Gray. The results from the SCB Core will be applied to the understanding of cancer etiology and potential cancer therapy through interactions with collaborators. These services are central to the goal of each Project to structurally characterize DNA repair complexes. MX provides atomic resolution information, while SAXS provides structural information on the conformations of DNA repair proteins and complexes in solution. The Core is centralized at the ALS because of the need for high flux, tunable wavelength X-rays for MX and SAXS studies. The Core also provides a critical mass of expertise needed for the difficult structural studies of flexible and modular proteins and complexes. The SCB Core, in collaboration with all six SBDR Projects, will generate insights into dynamic and coordinated assembly of large protein complexes involved in DNA repair processes.

Public Health Relevance

The SCB Core will provide to SBDR Projects expertise and facilities to structurally characterize DNA repair complexes by macromolecular crystallography, small angle X-ray scattering, and multi-angle light scattering. High resolution structures and structural analysis in solution are central to achieve the SBDR goal of mechanistic, predictive biology for improved cancer interventions that will be highly relevant to public health.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-0 (M1))
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Lawrence Berkeley National Laboratory
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Sishc, Brock J; Davis, Anthony J (2017) The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer. Cancers (Basel) 9:
Dungrawala, Huzefa; Bhat, Kamakoti P; Le Meur, Rémy et al. (2017) RADX Promotes Genome Stability and Modulates Chemosensitivity by Regulating RAD51 at Replication Forks. Mol Cell 67:374-386.e5
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