TY - JOUR AB - Models of transcriptional regulation that assume equilibrium binding of transcription factors have been less successful at predicting gene expression from sequence in eukaryotes than in bacteria. This could be due to the non-equilibrium nature of eukaryotic regulation. Unfortunately, the space of possible non-equilibrium mechanisms is vast and predominantly uninteresting. The key question is therefore how this space can be navigated efficiently, to focus on mechanisms and models that are biologically relevant. In this review, we advocate for the normative role of theory—theory that prescribes rather than just describes—in providing such a focus. Theory should expand its remit beyond inferring mechanistic models from data, towards identifying non-equilibrium gene regulatory schemes that may have been evolutionarily selected, despite their energy consumption, because they are precise, reliable, fast, or otherwise outperform regulation at equilibrium. We illustrate our reasoning by toy examples for which we provide simulation code. AU - Zoller, Benjamin AU - Gregor, Thomas AU - Tkačik, Gašper ID - 12156 IS - 9 JF - Current Opinion in Systems Biology KW - Applied Mathematics KW - Computer Science Applications KW - Drug Discovery KW - General Biochemistry KW - Genetics and Molecular Biology KW - Modeling and Simulation SN - 2452-3100 TI - Eukaryotic gene regulation at equilibrium, or non? VL - 31 ER - TY - JOUR AB - Anti-silencing function 1 (ASF1) is a conserved H3-H4 histone chaperone involved in histone dynamics during replication, transcription, and DNA repair. Overexpressed in proliferating tissues including many tumors, ASF1 has emerged as a promising therapeutic target. Here, we combine structural, computational, and biochemical approaches to design peptides that inhibit the ASF1-histone interaction. Starting from the structure of the human ASF1-histone complex, we developed a rational design strategy combining epitope tethering and optimization of interface contacts to identify a potent peptide inhibitor with a dissociation constant of 3 nM. When introduced into cultured cells, the inhibitors impair cell proliferation, perturb cell-cycle progression, and reduce cell migration and invasion in a manner commensurate with their affinity for ASF1. Finally, we find that direct injection of the most potent ASF1 peptide inhibitor in mouse allografts reduces tumor growth. Our results open new avenues to use ASF1 inhibitors as promising leads for cancer therapy. AU - Bakail, May M AU - Gaubert, Albane AU - Andreani, Jessica AU - Moal, Gwenaëlle AU - Pinna, Guillaume AU - Boyarchuk, Ekaterina AU - Gaillard, Marie-Cécile AU - Courbeyrette, Regis AU - Mann, Carl AU - Thuret, Jean-Yves AU - Guichard, Bérengère AU - Murciano, Brice AU - Richet, Nicolas AU - Poitou, Adeline AU - Frederic, Claire AU - Le Du, Marie-Hélène AU - Agez, Morgane AU - Roelants, Caroline AU - Gurard-Levin, Zachary A. AU - Almouzni, Geneviève AU - Cherradi, Nadia AU - Guerois, Raphael AU - Ochsenbein, Françoise ID - 9018 IS - 11 JF - Cell Chemical Biology KW - Clinical Biochemistry KW - Molecular Medicine KW - Biochemistry KW - Molecular Biology KW - Pharmacology KW - Drug Discovery SN - 2451-9456 TI - Design on a rational basis of high-affinity peptides inhibiting the histone chaperone ASF1 VL - 26 ER - TY - JOUR AB - Cross-metathesis reactions of α,β-unsaturated sulfones and sulfoxides in the presence of molybdenum and ruthenium pre-catalysts were tested. A selective metahesis reaction was achieved between functionalized terminal olefins and vinyl sulfones by using the ‘second generation’ ruthenium catalysts 1c–h while the highly active Schrock catalyst 1b was found to be functional group incompatible with vinyl sulfones. The cross-metathesis products were isolated in good yields with an excellent (E)-selectivity. Both the molybdenum and ruthenium-based complexes were, however, incompatible with α,β- and β,γ-unsaturated sulfoxides. AU - Michrowska, Anna AU - Bieniek, Michał AU - Kim, Mikhail AU - Klajn, Rafal AU - Grela, Karol ID - 13436 IS - 25 JF - Tetrahedron KW - Organic Chemistry KW - Drug Discovery KW - Biochemistry SN - 0040-4020 TI - Cross-metathesis reaction of vinyl sulfones and sulfoxides VL - 59 ER -