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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1-RPRB-0)
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Lawrence Berkeley National Laboratory
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Sung, Patrick (2018) Introduction to the Thematic Minireview Series: DNA double-strand break repair and pathway choice. J Biol Chem 293:10500-10501
Shen, Jianfeng; Ju, Zhenlin; Zhao, Wei et al. (2018) ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med 24:556-562
Sengupta, Shiladitya; Yang, Chunying; Hegde, Muralidhar L et al. (2018) Acetylation of oxidized base repair-initiating NEIL1 DNA glycosylase required for chromatin-bound repair complex formation in the human genome increases cellular resistance to oxidative stress. DNA Repair (Amst) 66-67:1-10
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Howes, Timothy R L; Sallmyr, Annahita; Brooks, Rhys et al. (2018) Erratum to ""Structure-activity relationships among DNA ligase inhibitors; characterization of a selective uncompetitive DNA ligase I inhibitor"" [DNA Repair 60C (2017) 29-39]. DNA Repair (Amst) 61:99
Bhattacharyya, Sudipta; Soniat, Michael M; Walker, David et al. (2018) Phage Mu Gam protein promotes NHEJ in concert with Escherichia coli ligase. Proc Natl Acad Sci U S A 115:E11614-E11622

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