Article
Biochemistry & Molecular Biology
Cornelia E. Zorca, Armaan Fallahi, Sophie Luo, Mohamed A. Eldeeb
Summary: Selective protein degradation is crucial for maintaining cellular homeostasis and is disrupted in various diseases. Targeted protein degradation approaches, based on existing cellular mechanisms, offer promising therapeutic strategies for regulating protein levels effectively.
Review
Chemistry, Multidisciplinary
Kristin M. Riching, Elizabeth A. Caine, Marjeta Urh, Danette L. Daniels
Summary: Targeted protein degradation is a crucial therapeutic approach that requires optimization of multiple parameters to achieve rapid degradation, high potency, and sustained target loss. Degradation is only the first milestone in degrader development, and understanding the dynamic cellular degradation profiles is essential for discovering effective therapeutic agents more efficiently.
CHEMICAL SOCIETY REVIEWS
(2022)
Article
Multidisciplinary Sciences
Meropi Bagka, Hyeonyi Choi, Margaux Heritier, Hanna Schwaemmle, Quentin T. L. Pasquer, Simon M. G. Braun, Leonardo Scapozza, Yibo Wu, Sascha Hoogendoorn
Summary: This study reveals that the cellular target of Hedgehog Pathway Inhibitor-1 is BET bromodomains by converting it into a bifunctional degrader. The strategy combines PROTACs and label-free quantitative proteomics to identify and validate the target, providing an effective approach for target deconvolution from phenotypic screens.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Tianyi Zhang, Chuanyang Liu, Wenying Li, Jingyu Kuang, Xin-yuan Qiu, Lu Min, Lingyun Zhu
Summary: This review summarizes the current state-of-the-art targeted protein degradation (TPD) technologies, including Trim-Away, LYTACs, and AUTACs, as well as their engineering efforts and developmental route. The general design principle, benefits, problems, and opportunities for improvement in TPD are analyzed, aiming to provide guidelines for the exploration, discovery, and future application of novel TPD tools.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
Review
Cell Biology
Yosup Kim, Eun-Kyung Kim, Yoona Chey, Min-Jeong Song, Ho Hee Jang
Summary: The proteasome is a multi-catalytic protease complex that regulates protein quality control. It selectively degrades cellular proteins through ubiquitination and plays a critical role in maintaining protein homeostasis. This article summarizes the proteasome's structure, regulatory mechanisms, proteins that control its activity, and its involvement in various diseases, chemoresistant cells, and cancer stem cells. Potential therapeutic modalities that target the ubiquitin-proteasome system are also discussed.
Review
Pharmacology & Pharmacy
Si-Min Qi, Jinyun Dong, Zhi-Yuan Xu, Xiang-Dong Cheng, Wei-Dong Zhang, Jiang-Jiang Qin
Summary: PROTAC technology is an effective method for degrading target proteins through the ubiquitin-proteasome system, with promising applications in cancer treatment. The first oral PROTACs have shown encouraging results in clinical trials, sparking greater enthusiasm for PROTAC research.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Fumiyo Ikeda
Summary: The ubiquitin-proteasomal system and the autophagy-lysosome system are two major degradation systems in mammalian cells. Ubiquitin not only regulates proteasomal degradation of substrates but also regulates the autophagy pathway. Ubiquitin plays a key role in autophagy regulation by recruiting cargos to phagophore in a ubiquitin-dependent manner.
Article
Biochemistry & Molecular Biology
Abramo J. Manfredonia, Daniel A. Kraut
Summary: The ubiquitin-proteasome system is responsible for protein degradation in eukaryotic cells. The study showed that degradation of ubiquitin-independent degrons (UbIDs) is slower and relies on loosely folded substrates. Furthermore, UbID degradation is ATP-independent.
Review
Biochemistry & Molecular Biology
Merav D. Shmueli, Daoud Sheban, Avital Eisenberg-Lerner, Yifat Merbl
Summary: Histones are key protein building blocks of chromatin, regulated by intricate mechanisms to control chromatin compaction and epigenetic regulation. Proteasome-dependent degradation, along with protein modifications, play roles in regulating histone stability, impacting cellular and physiological states.
Article
Multidisciplinary Sciences
Jennifer Cable, Eilika Weber-Ban, Tim Clausen, Kylie J. Walters, Michal Sharon, Daniel J. Finley, Yangnan Gu, John Hanna, Yue Feng, Sascha Martens, Anne Simonsen, Malene Hansen, Hong Zhang, Jonathan M. Goodwin, Alessio Reggio, Chunmei Chang, Liang Ge, Brenda A. Schulman, Raymond J. Deshaies, Ivan Dikic, J. Wade Harper, Ingrid E. Wertz, Nicolas H. Thoma, Mikolaj Slabicki, Judith Frydman, Ursula Jakob, Della C. David, Eric J. Bennett, Carolyn R. Bertozzi, Richa Sardana, Vinay V. Eapen, Serena Carra
Summary: Targeted protein degradation is essential for cellular function and development. This process involves tightly regulated protein degradation pathways to eliminate misfolded and aggregated proteins, adjust protein levels during cellular differentiation, and selectively eliminate target proteins. Understanding these pathways can provide insights into disease pathology and the development of novel therapeutics.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Ying Li, David Reverter
Summary: This review focuses on recent advances in the molecular mechanisms and specificities of DUB enzymes, highlighting examples where the regulatory mechanisms for DUBs have been understood in depth at the molecular level through structural biology. It also discusses strategies used by different DUB families to provide specificity in cleaving particular ubiquitin linkages, as well as recent progress in the development of drug compounds targeting DUB proteases and their correlation to various pathologies such as cancer and neurodegenerative diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Mashun Onishi, Koji Okamoto
Summary: Mitophagy is a crucial selective autophagy pathway that degrades dysfunctional mitochondria to maintain cellular health. Proper regulation of mitochondrial quantity and quality through mitophagy is essential for cellular energy balance, differentiation, and developmental processes. Defects in mitophagy can lead to various pathologies such as inflammation, tissue injury, neurodegeneration, and aging.
Article
Biochemistry & Molecular Biology
Muthukumar Elangovan, Jun Ka, Boryeong Pak, Woosoung Choi, Se-Ra Oh, Suk-Won Jin, Yung Joon Yoo
Summary: Ubiquitination plays an important regulatory role in angiogenesis, with E3 enzymes being extensively studied. The role of E2 enzymes in angiogenesis is less known. Through analysis of single-cell RNA sequencing data, UBE2V1 was identified as one of the most abundantly expressed E2s in endothelial cells. Inhibition of UBE2V1 affects endothelial cell proliferation, viability, morphogenesis, and migration, and is critical for FGF2-induced angiogenesis.
Article
Multidisciplinary Sciences
Yawei Ru, Xiaojie Yan, Bing Zhang, Lili Song, Qiqi Feng, Chen Ye, Zhili Zhou, Zhenzhen Yang, Yao Li, Zhenjian Zhang, Qianqian Li, Wenyi Mi, Cheng Dong
Summary: In this study, a new C-degron pathway, called the Gln/C-degron pathway, was discovered. The B30.2 domain of TRIM7 mediates the recognition of proteins with a C-terminal glutamine. The C-terminal residues of the substrate play a crucial role in C-degron recognition.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
Ecaterina Isacescu, Paul Chiroi, Oana Zanoaga, Andreea Nutu, Liviuta Budisan, Radu Pirlog, Atanas G. Atanasov, Ioana Berindan-Neagoe
Summary: Melanoma, the most aggressive type of skin cancer, still lacks highly effective treatments. This article aims to provide a comprehensive review on the molecular mechanisms of action regulated by polyphenols in melanoma cells. The review focuses on the in vitro and in vivo effects of polyphenol treatments on essential cellular pathways in tumors, as well as their role in regulating microRNAs and contributing to melanoma development. The goal is to provide a foundation for the development of polyphenol-based therapeutic agents in melanoma treatment.
Article
Multidisciplinary Sciences
Wantong Yao, Johnathon L. Rose, Wei Wang, Sahil Seth, Hong Jiang, Ayumu Taguchi, Jintan Liu, Liang Yan, Avnish Kapoor, Pingping Hou, Ziheng Chen, Qiuyun Wang, Luigi Nezi, Zhaohui Xu, Jun Yao, Baoli Hu, Piergiorgio F. Pettazzoni, I. Lin Ho, Ningping Feng, Vandhana Ramamoorthy, Shan Jiang, Pingna Deng, Grace J. Ma, Peter Den, Zhi Tan, Shu Xing Zhang, Huamin Wang, Y. Alan Wang, Angela K. Deem, Jason B. Fleming, Alessandro Carugo, Timothy P. Heffernan, Anirban Maitra, Andrea Viale, Haoqiang Ying, Samir Hanash, Ronald A. DePinho, Giulio F. Draetta
Article
Biochemistry & Molecular Biology
Filip Roudnicky, Yanjun Lan, Max Friesen, Gregor Dernick, Jitao David Zhang, Andreas Staempfli, Natalie Bordag, Antje Wagner-Golbs, Klaus Christensen, Martin Ebeling, Martin Graf, Mark Burcin, Claas Aiko Meyer, Chad A. Cowan, Christoph Patsch
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2019)
Article
Multidisciplinary Sciences
Filip Roudnicky, Bo Kyoung Kim, Yanjun Lan, Roland Schmucki, Verena Kuppers, Klaus Christensen, Martin Graf, Christoph Patsch, Mark Burcin, Claas Aiko Meyer, Peter D. Westenskow, Chad A. Cowan
SCIENTIFIC REPORTS
(2020)
Review
Oncology
Benjamin Haley, Filip Roudnicky
Article
Cell & Tissue Engineering
Takafumi Toyohara, Filip Roudnicky, Mary H. C. Florido, Toshiaki Nakano, Haojie Yu, Shunsuke Katsuki, Minjin Lee, Torsten Meissner, Max Friesen, Lance S. Davidow, Leon Ptaszek, Takaaki Abe, Lee L. Rubin, Alexandre C. Pereira, Masanori Aikawa, Chad A. Cowan
Article
Pathology
Filip Roudnicky, Cedric Poyet, Lorenz Buser, Karim Saba, Peter Wild, Vivianne Otto, Michael Detmar
AMERICAN JOURNAL OF PATHOLOGY
(2020)
Article
Multidisciplinary Sciences
Filip Roudnicky, Jitao David Zhang, Bo Kyoung Kim, Nikhil J. Pandya, Yanjun Lan, Lisa Sach-Peltason, Heloise Ragelle, Pamela Strassburger, Sabine Gruener, Mirjana Lazendic, Sabine Uhles, Franco Revelant, Oliv Eidam, Gregor Sturm, Verena Kueppers, Klaus Christensen, Leonard D. Goldstein, Manuel Tzouros, Balazs Banfai, Zora Modrusan, Martin Graf, Christoph Patsch, Mark Burcin, Claas A. Meyer, Peter D. Westenskow, Chad A. Cowan
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Oncology
Francesca Puca, Fei Yu, Caterina Bartolacci, Piergiorgio Pettazzoni, Alessandro Carugo, Emmet Huang-Hobbs, Jintan Liu, Ciro Zanca, Federica Carbone, Edoardo Del Poggetto, Joy Gumin, Pushan Dasgupta, Sahil Seth, Sanjana Srinivasan, Frederick F. Lang, Erik P. Sulman, Philip L. Lorenzi, Lin Tan, Mengrou Shan, Zachary P. Tolstyka, Maureen Kachman, Li Zhang, Sisi Gao, Angela K. Deem, Giannicola Genovese, Pier Paolo Scaglioni, Costas A. Lyssiotis, Andrea Viale, Giulio F. Draetta
Summary: The study reveals a high dependence of glioblastoma on mitochondrial fatty acid metabolism, specifically medium-chain acyl-CoA dehydrogenase (MCAD), with depletion leading to detrimental metabolic effects and cell death. The research highlights a potential therapeutic target in exploiting the key metabolic feature of GBM related to MCFA catabolism.
Article
Oncology
Jurgen Wichmann, Caroline Rynn, Thomas Friess, Jeannine Petrig-Schaffland, Martin Kornacker, Cornelia Handl, Jasmin Emmenegger, Jan Eckmann, Frank Herting, Nicolas Frances, Daniel Hunziker, Daniela Krummenacher, Dominik Ruettinger, Alison Ribeiro, Marina Bacac, Alessandro Brigo, David S. Hewings, Reinhard Dummer, Mitchell P. Levesque, Gabriel Schnetzler, Bruno Martoglio, James R. Bischoff, Piergiorgio Pettazzoni
Summary: A novel BRAF inhibitor (Compound Ia) has been developed, which showed elevated potency and selectivity in experimental settings and did not induce RAF paradoxical activation. It demonstrated superior activity compared to approved BRAFi in models of BRAF-mutated tumors.
CLINICAL CANCER RESEARCH
(2022)
Article
Genetics & Heredity
Mariana Galvao Ferrarini, Irene Ziska, Ricardo Andrade, Alice Julien-Laferriere, Louis Duchemin, Roberto Marcondes Cesar, Arnaud Mary, Susana Vinga, Marie-France Sagot
Summary: The paper presents a novel constrained-based method Totoro that integrates quantitative non-targeted metabolomic data of two different metabolic states into genome-wide metabolic models and predicts reactions most likely active during the transient state. Applied to real data, this approach was able to predict known active pathways and provide new insights into metabolism.
FRONTIERS IN GENETICS
(2022)
Article
Oncology
Ester Bonfill-Teixidor, Raffaella Iurlaro, Cornelia Handl, Jurgen Wichmann, Alexandra Arias, Isabel Cuartas, Jasmin Emmenegger, Andrea Romagnani, Luca Mangano, Thomas Lorber, Marco Berrera, Christina Godfried Sie, Fabian Kochl, Jan Eckmann, Romi Feddersen, Martin Kornacker, Gabriel Schnetzler, Marta Cicuendez, Esteban Cordero, Thomaz E. Topczewski, Abel Ferres-Pijoan, Josep Gonzalez, Francisco Martinez-Ricarte, Eva Munoz-Couselo, Josep Tabernero, James R. Bischoff, Piergiorgio Pettazzoni, Joan Seoane
Summary: A brain-penetrant BRAF inhibitor demonstrates potent activity in brain metastatic melanoma, even upon relapse following standard BRAF inhibitor therapy, supporting further investigation into its clinical utility.
Article
Biology
Nuria Gutierrez-Prat, Hedwig L. Zuberer, Luca Mangano, Zahra Karimaddini, Luise Wolf, Stefka Tyanova, Lisa C. Wellinger, Daniel Marbach, Vera Griesser, Piergiorgio Pettazzoni, James R. Bischoff, Daniel Rohle, Chiara Palladino, Igor Vivanco
Summary: MAPK inhibitors are important in the treatment of metastatic melanoma, but acquired resistance limits their effectiveness. Depletion of ERK phosphatase DUSP4 leads to hyperactivation of MAPK in mutant melanoma cells and down-regulation of key genes. This study provides a new approach for treating drug-resistant melanoma.
LIFE SCIENCE ALLIANCE
(2022)
Article
Biochemistry & Molecular Biology
Valentina Mengoli, Ilaria Ceppi, Aurore Sanchez, Elda Cannavo, Swagata Halder, Sarah Scaglione, Pierre-Henri Gaillard, Peter J. McHugh, Nathalie Riesen, Piergiorgio Pettazzoni, Petr Cejka
Summary: The Werner syndrome helicase, WRN, is a potential target for cancer therapy in microsatellite instability (MSI) cancers. This study demonstrates that WRN can efficiently unfold cruciform DNA structures and prevent their cleavage by a specific endonuclease. The DNA mismatch repair (MMR) complexes also decrease the level of cruciforms, with WRN and MMR proteins potentially cooperating. These findings provide mechanistic insights into genome instability in MSI cells and have implications for precision cancer therapy.
Article
Genetics & Heredity
Sophia Clara Maedler, Alice Julien-Laferriere, Luis Wyss, Miroslav Phan, Anthony Sonrel, Albert S. W. Kang, Eric Ulrich, Roland Schmucki, Jitao David Zhang, Martin Ebeling, Laura Badi, Tony Kam-Thong, Petra C. Schwalie, Klas Hatje
Summary: Besca is a toolkit that streamlines scRNA-seq analyses and deconvolutes genomic data according to best practices. It includes standard workflows and two modules for automated cell annotation and harmonized nomenclatures. Besca can be used to estimate cell type proportions and aids in acceleration, interoperability, reusability, and interpretability, meeting crucial demands in translational research and beyond.
NAR GENOMICS AND BIOINFORMATICS
(2021)