Publications

2025

• G-quadruplexes are promoter elements controlling nucleosome exclusion and RNA polymerase II pausing
  
  • Esnault Cyril
  • Zine El Aabidine Amal
  • Robert Marie-Cécile
  • Cucchiarini Anne
  • Magat Talha
  • Pigeot Alexia
  • Bouchouika Soumya
  • Garcia-Oliver Encar
  • Gawron Kevin
  • Basyuk Eugénia
  • Karpinska Magdalena A
  • Kozulic-Pirher Alja
  • Luo Yu
  • Verga Daniela
  • Mourad Raphael
  • Radulescu Ovidiu
  • Mergny Jean-Louis
  • Bertrand Edouard
  • Andrau Jean-Christophe
  Nature Genetics, Nature Publishing Group, 2025, 57 (8), pp.1981-1993. Despite their central role in transcription, it has been difficult to define universal sequences associated to eukaryotic promoters. Within chromatin context, recruitment of the transcriptional machinery requires promoter opening but how DNA elements could contribute to this process is unclear. Here, we show that G-quadruplex (G4) secondary DNA structures are highly enriched at mammalian promoters. G4s are located at the deepest point of nucleosome exclusion at promoters and correlate with maximum promoter activity. We found that experimental G4s exclude nucleosomes in vivo and in vitro while favouring strong positioning. At model promoters, impairing G4s affected both transcriptional activity and chromatin opening. G4 destabilization also resulted in an inactive promoter state and affected transition to effective RNA production. Finally, G4 stabilization resulted in global reduction of proximal promoter pausing. Altogether, our data introduce G4s as bona fide promoter elements allowing nucleosome exclusion and facilitating pause release by the RNA Polymerase II. (10.1038/s41588-025-02263-6)
  DOI : 10.1038/s41588-025-02263-6
• I-motif formation in the promoter region of the B-MYB proto-oncogene
  
  • Alves André
  • Miranda André
  • Zanin Irene
  • Richter Sara N
  • Mergny Jean-Louis
  • Cruz Carla
  International Journal of Biological Macromolecules, Elsevier, 2025, 296, pp.139582. Understanding the mechanisms of carcinogenesis is essential to combat cancer. The search for alternative targets for anticancer therapy has gained interest, particularly when focused on upstream pathways. This strategy is particularly relevant when the encoded target proteins are knownor believed -to be "undruggable", as has been reported for the B-MYB oncogene. This gene, which regulates survival and cell cycle regulation, is overexpressed in cancer and correlates with an unfavorable prognosis. In this study, we focused on the identification of the i-motif (iM) structures in the promoter region of B-MYB as a possible anticancer target, with a complete biophysical characterization and in cell formation assessment using iM-CUT&amp;Tag. Additionally, the interaction of the iM structures with a library of small molecules was investigated.</p></div> (10.1016/j.ijbiomac.2025.139582)
  DOI : 10.1016/j.ijbiomac.2025.139582
• Mechanism of Ultrafast Flavin Photoreduction in the Active Site of Flavoenzyme LSD1 Histone Demethylase
  
  • Zhuang Bo
  • Ramodiharilafy Rivo
  • Aleksandrov Alexey
  • Liebl Ursula
  • Vos Marten H
  Chemical Science, The Royal Society of Chemistry, 2025, 16, pp.338 - 344. Photoreduction of oxidized flavins has a functional role in photocatalytic and photoreceptor flavoproteins. In flavoproteins without light-dependent physiological functions, ultrafast, reversible flavin photoreduction is supposedly photoprotective by nature, and holds potential for nonnatural photocatalytic applications. In this work, we combine protein mutagenesis, ultrafast spectroscopy, molecular dynamics simulations and quantum mechanics calculations to investigate the nonfunctional flavin photoreduction in a flavoenzyme, lysine-specific demethylase 1 (LSD1) which is pivotal in DNA transcription. LSD1 harbors an oxidized flavin adenine dinucleotide (FAD) cofactor and multiple electron-donating residues in the active site. Upon photoexcitation, the FAD cofactor is photoreduced in &lt; 200 fs by electron transfer (ET) from nearby residue(s), and the charge pairs recombine in ca. 2 ps. Site-directed mutagenesis pinpoints a specific tryptophan residue, W751, as the primary electron donor, whereas a tyrosine residue, Y761, despite being located closer to the flavin ring, does not effectively contribute to the process. Based on a hybrid quantum–classical computational approach, we characterize the W751–FAD and Y761–FAD charge-transfer states (CTW751 and CTY761, respectively), as well as the FAD locally excited state (LEFAD), and demonstrate that the coupling between LEFAD and CTW751 is larger than those involving CTY761 by an order of magnitude, rationalizing the experimental observations. More generally, this work highlights the role of the intrinsic protein environment and details of donor–acceptor molecular configurations on the dynamics of short-range ET involving a flavin cofactor and amino acid residue(s). (10.1039/D4SC06857B)
  DOI : 10.1039/D4SC06857B
• Ultrafast dynamics of the UV-induced electronic relaxation in DNA guanine-thymine dinucleotides: from the Franck-Condon states to the minima of the potential energy surfaces
  
  • Petropoulos Vasilis
  • Martinez-Fernandez Lara
  • Uboldi Lorenzo
  • Maiuri Margherita
  • Cerullo Giulio
  • Balanikas Evangelos
  • Markovitsi Dimitra
  Physical Chemistry Chemical Physics, Royal Society of Chemistry, 2025. We study the DNA dinucleotide 5’-dGpdT-3’ (abbreviated as GT) as a model system for the relaxation of the electronic excited states in stacked nucleobases. Quantum chemistry calculations determine the Franck-Condon... (10.1039/D5CP00788G)
  DOI : 10.1039/D5CP00788G