We are studying the structural organization of DNA repair complexes that excise DNA damage and the functional consequences of disrupting these protein-protein interactions by mutation and small molecule inhibitors. Alternative pathways of repair are available for many types of DNA damage, and posttranslational modifications generated in response to DNA damage control the differential assembly of repair complexes, providing a mechanism for regulating pathway choice. Cancer-associated defects in DNA maintenance activities can be exploited therapeutically by targeting the remaining repair activities with mechanism-based inhibitors. Our work focuses on the mechanisms of repairing DNA single strand breaks generated by the base excision and nucleotide excision repair pathways. We are studying the physical assembly of DNA damage excision complexes in vitro and in cultured cells, and the mechanism of coupling DNA cleavage to end processing and ligation. Small angle x-ray scattering of purified DNA repair complexes reveals dynamic conformational states that we propose are important for handoffs of DNA repair intermediates to successive enzymes in a pathway. High resolution crystal structures and small molecule screening experiments are being used to predict and identify inhibitors of repair protein interactions, which are candidates for anti-tumor therapies and serve as reversible chemical probes of cellular physiology during DNA damage responses. This integrated approach takes advantage of the broad expertise of investigators in Projects 1, 2, and 6 for assays and biological materials, as well as the unique capabilities of the Expression and Molecular Biology Core and the Structural Cell Biology Core of the SBDR Program to produce proteins and structurally evaluate repair complexes.
DNA repair protein interactions are a promising target for cancer therapies that block essential repair activities in tumors with acquired mutations in alternative pathways. We are evaluating the functions of specific protein interactions and developing proof-of-concept inhibitors that may have therapeutic potential.
|Sishc, Brock J; Davis, Anthony J (2017) The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer. Cancers (Basel) 9:|
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|Sugitani, Norie; Voehler, Markus W; Roh, Michelle S et al. (2017) Analysis of DNA binding by human factor xeroderma pigmentosum complementation group A (XPA) provides insight into its interactions with nucleotide excision repair substrates. J Biol Chem 292:16847-16857|
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|Tsutakawa, Susan E; Thompson, Mark J; Arvai, Andrew S et al. (2017) Phosphate steering by Flap Endonuclease 1 promotes 5'-flap specificity and incision to prevent genome instability. Nat Commun 8:15855|
|Shi, Yuqian; Hellinga, Homme W; Beese, Lorena S (2017) Interplay of catalysis, fidelity, threading, and processivity in the exo- and endonucleolytic reactions of human exonuclease I. Proc Natl Acad Sci U S A 114:6010-6015|
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