Cancer & Gene Editing
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Rationale
Although discovered as restriction factors against HIV-1, certain members of the human enzyme family Apolipoprotein B mRNA-Editing Enzyme Catalytic Polypeptide (APOBEC) have been implicated in both the development and the disease severity of various cancers. APOBECs are deaminases that cause mutations in DNA (and some also in RNA). Despite highly similar overall structures, APOBECs have varying substrate specificity and activity. Characterizing molecular interactions involved in APOBEC substrate binding and recognition can inform specific targeting of these enzymes to develop new drug treatments for various types of cancers.
What we're doing
Our work has determined and analyzed structural and dynamic interactions of APOBECs with substrate DNA. We are now using this knowledge to design oligo-based inhibitors. Due to their ability to introduce specific mutations in DNA, APOBECs have attracted much attention recently and we, as well as others, are exploring APOBECs in engineering tools in gene editing technologies.
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Publication Highlights
Kouno, T.; Silvas, T.V.; Hilbert, B.J.; Shandilya, S.M.D.; Bohn, M.F.; Kelch, B.A.; Royer, W.E.; Somasundara, M.; Kurt Yilmaz, N.; Matruo, H.; Schiffer, C.A. “Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity” Nature Communications, 15024 (2017).
Silvas, T.V.; Hou, S.; Myint, W.; Nalivaika, E.; Somasundaran, M.; Kelch, B.A.; Matsuo, H.; Kurt Yilmaz, N.; Schiffer, C.A. “Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions” Scientific Reports, Vol. 8, Iss. 1, p. 7511 (2018).
Hou S, Silvas T, Leidner F, Nalivaika EA, Matsuo H, Kurt Yilmaz N, Schiffer CA. “Structural analysis of the active site and DNA binding of human cytidine deaminase APOBEC3B” Journal of Chemical Theory and Computation, Vol. 15, Iss. 1, pp 637–647 (2019).
Hou S, Lee JM, Myint W, Matsuo H, Kurt Yilmaz N, Schiffer CA. “Structural Basis of Substrate Specificity in Human Cytidine Deaminase Family APOBEC3s” Journal of Biological Chemistry, Vol. 297, Iss. 2, 100909 (2021).