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Patrick SCHULTZ

My major scientific interest is to understand the structure-function relationships of multi-protein complexes involved in transcription regulation, DNA repair, and in the modulation of chromatin structure. In my team we use a combination of biochemistry, yeast genetics, molecular biology and structural biology methods in particular high resolution cryo-EM the implementation of which I pioneered in Strasbourg University in the early 90’. We obtained structural and functional insights into the transcription/DNA repair factor TFIIH and provided the first structural structural models of the general transcription factor TFIID from yeast by working out subunit maps of the complexes. In collaboration with I. Berger (EMBL, Grenoble) we determined a 10 Å resolution structure of a recombinant human core-TFIID subcomplex consisting of a subset of 5 subunits and showing two-fold symmetry (Bieniossek et al., Nature, 2013). We demonstrated that binding of the TAF8/TAF10 heterodimer breaks the original symmetry of core-TFIID and analyzed the incorporation of TAF2 into core-TFIID (Trowitzsch et al., Nature Commun, 2015). We published the first near atomic model of yeast TFIID bound to a gene promoter (Kolesnikova et al., Nature Commun, 2018). We could position existing subunit atomic structures, propose a model for the subunit organization of TFIID, and identify two promoter DNA interaction domains separated by 35 bp. This work provided new insights into the way TFIID recognizes and binds to gene promoters. We determined the first model of SAGA revealing the modular organization of the complex into functional modules (Wu et al., Mol. Cell, 2004, Durand et al., structure, 2014). We positioned the histone acetyl transferase (HAT) module and showed that it is located in a flexible arm of SAGA. We determined the first cryo-EM model of SAGA and revealed the structural organization of Tra1 at 5.7 Å resolution (Sharov et al., Nature Commu. 2017). At this resolution, we could trace the main chain of the 430 KDa Tra1 protein, which is key to signal cellular events to the transcription machinery. Recently we determined an atomic model of SAGA (Papai et al., 2020) showing that SAGA and TFIID share a similar TBP-delivery machine composed of a deformed octamer of histone fold containing proteins. We show how TBP is sterically hindered to bind DNA, an inhibition released by TFIIA. This structure showing at atomic details the mode of interaction of TBP with SAGA was cited in several reviews and was awarded the Grandes Avancées Françaises en Biologie distinction by the French academy of sciences. This expertise in transcription, molecular and structural biology of macromolecular assemblies involved in transcription is central to the current project. Top five publications from the last 5 years I contributed to 106 peer-reviewed publications and have an H-index of 36 with 5056 citations. 1. Papai, G., Frechard, A., Kolesnikova, O., Crucifix, C., Schultz, P., and Ben-Shem, A. (2020) Structure of SAGA and mechanism of TBP deposition on gene promoters, Nature 577, 711-716. 2. Kolesnikova O, Ben-Shem A, Luo J, Ranish J, Schultz P, Papai G (2018) Molecular structure of promoter-bound yeast TFIID. Nature communications 9: 4666 3. Bednar J, Garcia-Saez I, Boopathi R, Cutter AR, Papai G, Reymer A, Syed SH, Lone of IN, Tonchev O, Crucifix C, Menoni H, Papin C, Skoufias DA, Kurumizaka H, Lavery R, Hamiche A, Hayes JJ, Schultz P, Angelov D, Petosa C, Dimitrov S (2017) Structure and Dynamics of a 197 bp Nucleosome in Complex with Linker Histone H1. Molecular cell 66: 729 4. Sharov G, Voltz K, Durand A, Kolesnikova O, Papai G, Myasnikov AG, Dejaegere A, Ben Shem A, Schultz P (2017) Structure of the transcription activator target Tra1 within the chromatin modifying complex SAGA. Nature communications 8: 1556 5. Pilsl M, Crucifix C, Papai G, Krupp F, Steinbauer R, Griesenbeck J, Milkereit P, Tschochner H, Schultz P (2016) Structure of the initiation-competent RNA polymerase I and its implication for transcription. Nature communications 7: 12126

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