Article
Biochemistry & Molecular Biology
Di Bai, Song-Wang Shan, Xin Zhang, Yan Li, Jie Xie, Wen-Qiang Wu
Summary: In this study, the folding, dynamics induced by environment, and protein-catalyzed unfolding of plant telomeric G4s were comprehensively studied. It was found that various plant telomeric sequences can fold into G4 structures, and the stability of G4s in dilute solution is decreased by both 5' and 3' ssDNA. Molecular crowding promotes the formation of parallel structures for three-layer G4s and increases the stability of all selected G4s. AtRecQ2 helicase can resolve the stable parallel structure of typical plant telomeric G4 in crowded solution, while ssDNA binding protein AtRPA cannot. Furthermore, AtRecQ2 unwinds the structure more efficiently in the presence of AtRPA. These results expand our understanding of the structures and dynamics of plant telomeric G4s.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biochemical Research Methods
Yue Wang, Guo Li, Tong Meng, Lin Qi, Hui Yan, Zhiguo Wang
Summary: The designed monohydrazone derivative shows specific preference in binding and stabilizing parallel human telomeric G4. The end-stacking binding mode is preferred, with van der Waals interactions playing a leading role in determining binding affinity. These findings support the design of novel selective stabilizers targeting telomeric G4s.
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
(2022)
Article
Physics, Multidisciplinary
Yun-Qiang Bian, Feng Song, Zan-Xia Cao, Jia-Feng Yu, Ji-Hua Wang
Summary: The hybrid atomistic structure-based model has been shown effective in investigating G-quadruplex folding and complementing the folding mechanism of human telomeric sequence Htel24. Real-time folding rate of Htel24 was estimated using a Markov state model, revealing potential fast folding on the order of milliseconds between hybrid-1 and hybrid-2 G-quadruplex conformations. A comparison with structure-based simulations identified more metastable states participating in the formation of hybrid-1 and hybrid-2 conformations, suggesting that coupling hybrid atomistic structure-based model and conventional all-atom model can provide deeper insights into DNA G-quadruplex folding dynamics. This multiscale computational framework may be valuable for studying complex biomolecular processes with large conformational changes.
Article
Biochemistry & Molecular Biology
Xupeng Yu, Sean Gray, Helder C. Ferreira
Summary: The POT-3 protein in Caenorhabditis elegans is found to bind the telomeric G-strand and affects telomere length and telomeric C-circle formation, showing differences with the closely related POT-2 protein in terms of binding sites and function.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Conner L. Olson, Alexandra T. Barbour, Thomas A. Wieser, Deborah S. Wuttke
Summary: G-quadruplexes (G4s) are stable secondary structures that form in guanine-rich regions of single-stranded nucleic acids and pose challenges for DNA maintenance. The proteins Replication Protein A (RPA) and CTC1-STN1-TEN1 (CST) are involved in managing G4s at telomeres. RPA tightly binds telomeric G4s, while CST's ability to bind G-rich ssDNA is inhibited by the presence of G4s. RPA's greater cellular abundance and its collaborative DNA-binding domains suggest that it may be the primary protein complex responsible for resolving G4s at telomeres.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Cell Biology
Shalu Sharma, Ananda Kishore Mukherjee, Shuvra Shekhar Roy, Sulochana Bagri, Silje Lier, Meenakshi Verma, Antara Sengupta, Manish Kumar, Gaute Nesse, Deo Prakash Pandey, Shantanu Chowdhury
Summary: The study reveals that the telomere-repeat-binding-factor TRF2 binds to G-quadruplexes in the hTERT promoter, leading to H3K27 trimethylation and repression of hTERT in both cancer and normal cells. Two highly recurrent hTERT promoter mutations found in many cancers disrupt G-quadruplexes, resulting in loss of TRF2 binding.
Article
Biochemistry & Molecular Biology
Yu-Cheng Liu, Dah-Yen Yang, Sheh-Yi Sheu
Summary: G-quadruplexes have become attractive drug targets in cancer therapy, but the polymorphic nature of their structures makes understanding their conformational conversion mechanisms challenging. This study used molecular dynamics simulation to show that as salt concentration increases, the mechanism of conformational conversion shifts from multi-pathway to sequential pathways, with conformational conversion being more feasible upon K+ binding compared to Na+ binding in high-salt solutions.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Chemistry, Multidisciplinary
Wenxuan Hu, Haitao Jing, Wenqiang Fu, Zengrong Wang, Jiang Zhou, Na Zhang
Summary: In this study, a new type of G-quadruplex structure, parallel homomeric bimolecular G-quadruplex, was demonstrated to undergo strand displacement reaction with short G-rich DNA fragments at room temperature, resulting in the formation of a parallel heteromeric trimolecular G-quadruplex. This provides new insights into the development of complex architectures in G-quadruplex-based DNA nanotechnology.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemistry & Molecular Biology
Yasmeen Khan, Talat Azam, Jenifer Seematti Sundar, Souvik Maiti, Mary K. Ekka
Summary: Nucleolin (NCL) is a nucleic acid-binding protein that can bind to various DNA and RNA structures, including single-stranded and double-stranded DNA/RNA, hairpin, loops, and G-quadruplex structures. G-quadruplex structures are mainly formed in promoter, telomeric, and untranslated regions of the genome, and affect replication, transcription, and translation processes. Our study demonstrates that the 21nt G-quadruplex-forming region of telomeric DNA and TERRA RNA can bind to NCL, and the RRM1234 domains destabilize the telomeric G-quadruplex structure. We also find that the RNA G-quadruplex preferentially binds to the RRM3 and RRM4 domains. Our findings provide insights into the binding preferences of RRM domains towards G-quadruplex structures and their subsequent effect on stability.
Article
Biochemistry & Molecular Biology
Andrei G. Loiko, Alexander Sergeev, Adelya Genatullina, Mayya Monakhova, Elena A. Kubareva, Nina G. Dolinnaya, Elizaveta S. Gromova
Summary: This study reveals a potential link between G-quadruplex formation and the function of DNA methyltransferase Dnmt3a in mammals. G4s may play a role in epigenetic regulation by affecting the methylation of specific CpG sites and modulating the enzyme activity. Possible mechanisms include sequestration of Dnmt3a at G4 structures and disruption of Dnmt3a oligomerization on DNA.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Domen Oblak, Hadzi, Crtomir Podlipnik, Jurij Lah
Summary: The authors investigated the (un)folding and binding process of a human telomeric fragment with ligands through calorimetry and spectroscopy. The results showed that the presence of specific ligands can alter the topology of G-quadruplex nucleic acids. By analyzing thermodynamic parameters and conducting molecular modeling, the driving forces behind the topological transformations were clarified.
Article
Biochemistry & Molecular Biology
Huajun Zhang, Shuyan Dai, Xujun Liang, Jun Li, Yongheng Chen
Summary: This study demonstrates that FOXM1 prefers binding tandem DNA sites, and this binding preference may be driven by intermolecular protein-protein interactions.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Anirban Ghosh, Marko Trajkovski, Marie-Paule Teulade-Fichou, Valerie Gabelica, Janez Plavec
Summary: Human telomeric G-quadruplex DNA structures are attractive targets for anticancer drugs. However, the polymorphism of the target complicates drug design. This study reports the discovery of a G-quadruplex ligand that can completely change the fold of the DNA structure, providing valuable insights into the coordination structure of G-quadruplexes.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Sampat N. Satapathy, Partha S. Nial, Kiran D. Tulsiyan, Umakanta Subudhi
Summary: Recently, the importance of light rare earth elements (LREEs) in modern technologies has increased. This study discovered the formation of G-quadruplex in human telomeric variants in the presence of micromolar concentrations of LREEs. The results suggest a binding stoichiometry of 2:1 between lanthanide ions and telomeric variants, with LREE ions coordinating between adjacent G-quartets.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2024)
Article
Biochemistry & Molecular Biology
Adam J. Pollak, Luyi Zhao, Timothy A. Vickers, Ian J. Huggins, Xue-Hai Liang, Stanley T. Crooke
Summary: Non-CpG PS-ASOs can activate the innate immune system, but may lead to undesired outcomes. The innate immune responses of PS-ASOs can vary depending on their modifications and sequence. Pro-inflammatory PS-ASOs require TLR9 signaling, but their innate immunity is not correlated with their binding affinity with TLR9. Additionally, non-inflammatory PS-ASOs can reduce the innate immune responses of pro-inflammatory PS-ASOs, suggesting interaction with TLR9.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Cell Biology
Sara Iachettini, Fabio Ciccarone, Carmen Maresca, Carmen D' Angelo, Eleonora Petti, Serena Di Vito, Maria Rosa Ciriolo, Pasquale Zizza, Annamaria Biroccio
Summary: TERF2 is a telomeric protein that plays a crucial role in tumor formation and progression. This study uncovers a novel function of TERF2 in regulating the autophagic process and reveals its interaction with HMGB1 as functional for protein localization.
Article
Chemistry, Multidisciplinary
Linda Cerofolini, Kiefer O. Ramberg, Luis C. Padilla, Pawel Antonik, Enrico Ravera, Claudio Luchinat, Marco Fragai, Peter B. Crowley
Summary: Protein frameworks are emerging biomaterials with potential medical and technological applications. This study introduces a complementary strategy using solid-state NMR analysis to characterize low-crystallinity frameworks, specifically focusing on a microcrystalline protein-macrocycle framework and its rehydrated freeze-dried form.
CHEMICAL COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Linda Cerofolini, Kristian Vasa, Elisa Bianconi, Maria Salobehaj, Giulia Cappelli, Alice Bonciani, Giulia Licciardi, Anna Perez-Rafols, Luis Padilla-Cortes, Sabrina Antonacci, Domenico Rizzo, Enrico Ravera, Caterina Viglianisi, Vito Calderone, Giacomo Parigi, Claudio Luchinat, Antonio Macchiarulo, Stefano Menichetti, Marco Fragai
Summary: Several protein-drug conjugates are currently used in cancer therapy, relying on covalently attached cytotoxic organic compounds or non-covalent interactions. Human transthyretin (TTR) has been identified as a potential carrier protein for cytotoxic drug delivery. This study demonstrates the importance of integrating multiple biophysical and structural techniques, such as microscale thermophoresis, X-ray crystallography, and NMR. Solid-state NMR is particularly valuable in revealing ligand binding effects and their impact on macromolecular complex stability.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biochemistry & Molecular Biology
Chiara Platella, Francesca Ghirga, Domenica Musumeci, Deborah Quaglio, Pasquale Zizza, Sara Iachettini, Carmen D'Angelo, Annamaria Biroccio, Bruno Botta, Mattia Mori, Daniela Montesarchio
Summary: In this study, five natural compounds were investigated as analogs of promising G-quadruplex-targeting ligands to identify highly effective and selective anticancer candidates. Among them, Dicentrine was found to be the most effective ligand for telomeric and oncogenic G-quadruplexes, showing good selectivity. In-depth studies demonstrated that Dicentrine thermally stabilizes G-quadruplexes without affecting the control duplex, with higher affinity for G-quadruplex structures. Molecular dynamics simulations indicated that Dicentrine preferentially binds the G-quadruplex groove or the outer G-tetrad. Biological assays confirmed that Dicentrine promotes potent and selective anticancer activity by inducing cell cycle arrest through apoptosis, targeting G-quadruplex structures at telomeres.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Milana Bazayeva, Andrea Giachetti, Marco Pagliai, Antonio Rosato
Summary: Classical molecular dynamics (MD) simulations are commonly used to study the behavior of zinc(II)-proteins at the atomic level. In this study, the accuracy of two force fields (ZAFF and NBFF) in reproducing the dynamic behavior of zinc(II)-proteins was assessed using six zinc-fingers as benchmark. The results indicated that both force fields can accurately reproduce protein dynamics with comparable accuracy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell & Tissue Engineering
Maria Rosaria Ambrosio, Teresa Migliaccio, Fabiana Napolitano, Sarah Di Somma, Giovanni Maneli, Jussara Amato, Bruno Pagano, Antonio Randazzo, Giuseppe Portella, Pietro Formisano, Anna Maria Malfitano
Summary: In this study, the role of G4 motifs in adipogenic differentiation was investigated using human adipose-derived mesenchymal stem cells (ASCs). The results showed that G4 structures were increased in differentiated adipocytes compared to their precursors, and treatment with the G4 ligand Braco-19 reduced G4 content in the mature adipocytes. Furthermore, Braco-19 caused morphological changes and reduced lipid droplet formation and key gene expression in the mature adipocytes. These findings reveal a new role of G4 motifs in human adipocyte differentiation.
STEM CELL RESEARCH & THERAPY
(2023)
Article
Biochemistry & Molecular Biology
Silvia Trombetti, Nunzia Iaccarino, Patrizia Riccio, Raffaele Sessa, Rosa Catapano, Marcella Salvatore, Stelina Luka, Sergio de Nicola, Paola Izzo, Sante Roperto, Pasqualino Maddalena, Antonio Randazzo, Michela Grosso
Summary: Ferroptosis is a regulated cell death involving lipid peroxidation. GPX4 plays a central role in its regulation. Ferroptosis is connected to lipid metabolism, cancer onset, and drug resistance. GATA-1 isoforms, particularly GATA-1(S), are involved in hematological malignancies. Overexpression of GATA-1(S) prevents ferroptosis in leukemia cells. Targeting ferroptosis is a promising strategy to overcome drug resistance in hematological malignancies.
Article
Biochemical Research Methods
Vincenzo Laveglia, Milana Bazayeva, Claudia Andreini, Antonio Rosato
Summary: This study develops a bioinformatics tool called Master of Metals (MOM) to predict zinc(II)-binding sites in protein 3D structures. By using the structural models generated by AlphaFold as input, the tool can annotate the entire proteome of an organism within a few hours. It achieves a precision of approximately 76% when applied to the yeast proteome.
Review
Chemistry, Medicinal
Francesca Romano, Anna Di Porzio, Nunzia Iaccarino, Gelsomina Riccardi, Ritamaria Di Lorenzo, Sonia Laneri, Bruno Pagano, Jussara Amato, Antonio Randazzo
Summary: Modulation of G-quadruplex (G4) formation has been proposed as a powerful tool for cancer treatment through the control of oncogene expression. This review provides an overview of current knowledge on G4s in human oncogene promoters and the most representative G4-binding ligands. Targeting G4s has the potential to develop novel and highly specific anticancer drugs capable of selectively impacting gene expression.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2023)
Article
Spectroscopy
Francesco D'Amico, Raffaele Graziano, Federica D'Aria, Pasquale Russomanno, Silvia Di Fonzo, Jussara Amato, Bruno Pagano
Summary: Epigenetic modifications of DNA and G-quadruplex structures are closely related and can be studied using UV resonance Raman spectroscopy. This study demonstrates that UVRR spectroscopy can detect spectral changes in G-quadruplex structures and indirectly identify modifications in guanine glycosidic conformations and changes induced by H-bond formation or hydration. These findings support the usefulness of UVRR spectroscopy for studying G-quadruplex structures in biologically relevant conditions.
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
(2023)
Article
Biochemistry & Molecular Biology
Greta Donati, Vincenzo Maria D'Amore, Pasquale Russomanno, Linda Cerofolini, Jussara Amato, Simona Marzano, Maria Salobehaj, Domenico Rizzo, Giulia Assoni, Alfonso Carotenuto, Valeria La Pietra, Daniela Arosio, Pierfausto Seneci, Marco Fragai, Diego Brancaccio, Francesco Saverio Di Leva, Luciana Marinelli
Summary: The PD-1/PD-L1 axis is crucial in evading the immune system in cancers, and anti-PD-1/PD-L1 antibodies have been extensively studied in clinical trials. However, the development of small molecules as anti-PD-L1 drugs faces certain limitations. This study utilized theoretical and experimental approaches to gain insights into the molecular interactions between biphenyl-based compounds and human and murine PD-L1, providing valuable information for the design of next-generation anti-PD-L1 molecules.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2023)
Article
Chemistry, Analytical
Francesca Romano, Enza Di Gregorio, Gelsomina Riccardi, Chiara Furlan, Nicola Cavallini, Francesco Savorani, Anna Di Porzio, Stefano De Tito, Antonio Randazzo, Eliana Gianolio, Nunzia Iaccarino
Summary: In this study, the effects of multiple administrations of linear and macrocyclic gadolinium-based contrast agents (GBCAs) on the metabolic pathways in healthy mice were investigated. The results showed that the linear GBCA had a significant impact on organs such as the brain, cerebellum, and liver, while the macrocyclic GBCA had a smaller effect. This study paves the way for the safer use of commercially available GBCAs and the development of new GBCAs with lower toxicity.
Meeting Abstract
Biochemistry & Molecular Biology
Anna Perez-Rafols, Guillermo Perez Ropero, Rosa Anahi Higuera, Linda Cerofolini, Marco Fragai, Tommaso Martelli