Ravichandran, Mirunalini and Rafalski, Dominik and Davies, Claudia I. and Ortega-Recalde, Oscar and Nan, Xinsheng and Glanfield, Cassandra R. and Kotter, Annika and Misztal, Katarzyna and Wang, Andrew H. and Wojciechowski, Marek and Razew, Michal and Mayyas, Issam M. and Kardailsky, Olga and Schwartz, Uwe and Zembrzycki, Krzysztof and Morison, Ian M. and Helm, Mark and Weichenhan, Dieter and Jurkowska, Renata Z. and Krueger, Felix and Plass, Christoph and Zacharias, Martin and Bochtler, Matthias and Hore, Timothy A. and Jurkowski, Tomasz P. (2022) Pronounced sequence specificity of the TET enzyme catalytic domain guides its cellular function. SCIENCE ADVANCES, 8 (36): eabm2427. ISSN 2375-2548,
Full text not available from this repository. (Request a copy)Abstract
TET (ten-eleven translocation) enzymes catalyze the oxidation of 5-methylcytosine bases in DNA, thus driving active and passive DNA demethylation. Here, we report that the catalytic domain of mammalian TET enzymes favor CGs embedded within basic helix-loop-helix and basic leucine zipper domain transcription factor-binding sites, with up to 250-fold preference in vitro. Crystal structures and molecular dynamics calculations show that sequence preference is caused by intrasubstrate interactions and CG flanking sequence indirectly affecting enzyme conformation. TET sequence preferences are physiologically relevant as they explain the rates of DNA demethylation in TET-rescue experiments in culture and in vivo within the zygote and germ line. Most and least favorable TET motifs represent DNA sites that are bound by methylation-sensitive immediate-early transcription factors and octamer-binding transcription factor 4 (OCT4), respectively, illuminating TET function in transcriptional responses and pluripotency support.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DNA METHYLATION; NAIVE PLURIPOTENCY; MAMMALIAN DNA; DEMETHYLATION; ERASURE; 5-METHYLCYTOSINE; EXPRESSION; INSIGHT; TDG; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 01 Feb 2024 11:16 |
| Last Modified: | 01 Feb 2024 11:16 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58676 |
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