A zinc linchpin motif in the MUTYH glycosylase interdomain connector is required for efficient repair of DNA damage

Lisa M. Engstrom, Megan K. Brinkmeyer, Yang Ha, Alan G. Raetz, Britt Hedman, Keith O. Hodgson, Edward I. Solomon, Sheila S. David

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Mammalian MutY glycosylases have a unique architecture that features an interdomain connector (IDC) that joins the catalytic N-terminal domain and 8-oxoguanine (OG) recognition C-terminal domain. The IDC has been shown to be a hub for interactions with protein partners involved in coordinating downstream repair events and signaling apoptosis. Herein, a previously unidentified zinc ion and its coordination by three Cys residues of the IDC region of eukaryotic MutY organisms were characterized by mutagenesis, ICP-MS, and EXAFS. In vitro kinetics and cellular assays on WT and Cys to Ser mutants have revealed an important function for zinc coordination on overall protein stability, iron-sulfur cluster insertion, and ability to mediate DNA damage repair. We propose that this "zinc linchpin" motif serves to structurally organize the IDC and coordinate the damage recognition and base excision functions of the C- and N-terminal domains.

Original languageEnglish (US)
Pages (from-to)7829-7832
Number of pages4
JournalJournal of the American Chemical Society
Volume136
Issue number22
DOIs
StatePublished - Jun 4 2014

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    Engstrom, L. M., Brinkmeyer, M. K., Ha, Y., Raetz, A. G., Hedman, B., Hodgson, K. O., Solomon, E. I., & David, S. S. (2014). A zinc linchpin motif in the MUTYH glycosylase interdomain connector is required for efficient repair of DNA damage. Journal of the American Chemical Society, 136(22), 7829-7832. https://doi.org/10.1021/ja502942d