Review
Biology
Michael Ohh, Cassandra C. Taber, Fraser G. Ferens, Daniel Tarade
Summary: von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome caused by mutations in pVHL and disruption of HIF alpha degradation, and the understanding of its genotype-phenotype relationship is crucial for future management of VHL patients.
Article
Biochemistry & Molecular Biology
Giorgia F. Camagni, Giovanni Minervini, Silvio C. E. Tosatto
Summary: The Prolyl Hydroxylases (PHDs) are a family of enzymes that regulate cell oxygen-sensing by hydroxylating hypoxia-inducible transcription factors alpha (HIFs-alpha) and promoting their degradation. Hypoxia inhibits PHDs activity, leading to HIFs-alpha stabilization and cell adaptation to low oxygen levels. The different isoforms of PHDs have varying effects on tumor progression. Molecular dynamics simulations, conservation analysis, and binding free energy calculations were used to study the binding properties and substrate affinity of PHD2 with HIF-1 alpha and HIF-2 alpha. The findings suggest that the PHD2 C-terminus may play a role in regulating PHD activity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Seung Han Son, Min Young Kim, Young Su Lim, Hyeon Cheol Jin, June Ho Shin, Jae Kyu Yi, Sungwoo Choi, Mi Ae Park, Ji Hyung Chae, Ho Chul Kang, Young Jin Lee, Vladimir N. Uversky, Chul Geun Kim
Summary: This study uncovers a novel mechanism of CP2c degradation through SUMO1/PSME3/20S proteasome pathway and its significance in cell cycle progression.
Article
Biochemistry & Molecular Biology
Hyun-Yoo Joo, Jin Kyu Jung, Mi-Yeon Kim, Seon Rang Woo, Jae Min Jeong, Eun-Ran Park, Yong-Min Kim, Joong-Jean Park, Joon Kim, Miyong Yun, Hyun-Jin Shin, Kee-Ho Lee
Summary: This study reveals that the high concentration of pyruvate in the culture medium can affect the stability of HIF-1α, and NADH serves as a signal for the degradation of HIF-1α under chronic hypoxia through the SIRT1 and VHL signaling pathway. This degradation leads to a reduction in hypoxia-enhanced invasion and angiogenic activities. Additionally, the study demonstrates that VHL is involved in the degradation of HIF-1α through recognition of hydroxylation in normoxia and acetylation in hypoxia.
CELL AND BIOSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Wenguang He, Sarah Batty-Stuart, Jeffrey E. Lee, Michael Ohh
Summary: The study demonstrates that both hydroxyprolines in HIF-1 alpha ODD bind to the same interface on VHL with similar affinity; VHL binding affinity to ODD remains relatively unchanged whether one or two hydroxyprolines are present; ODD with two hydroxyprolines can accommodate two VHLs, and the ubiquitination rate is comparable between ODD with one or two hydroxyprolines. However, the two hydroxyprolines show distinct contributions to the intracellular stability of HIF-1 alpha ODD.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Review
Cell Biology
Xianyi Meng, Ben Wielockx, Martina Rauner, Aline Bozec
Summary: Hypoxia-inducible factors (HIFs) play a crucial role in regulating bone metabolism, angiogenesis, and inflammation, with significant impact on osteoclast activity. Their tight regulation by tissue microenvironments highlights their importance in bone pathologies.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Immunology
Jinwei Zhang, Xiaoqian Wu, Jideng Ma, Keren Long, Jing Sun, Mingzhou Li, Liangpeng Ge
Summary: Hypoxia and HIF signaling have important regulatory roles in cell biology, but their role in B cell biology is still controversial. Studies have found that hypoxia niches exist in different developmental stages of B cells, suggesting that hypoxia and HIF signaling may play a crucial role in the development, metabolism, and function of B cells. A better understanding of the role of hypoxia in B cell-mediated adaptive immunity could provide new strategies for vaccine adjuvant research and the treatment of immunity-related or infectious diseases.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Gastroenterology & Hepatology
Peter A. C. Wing, Peter Jianrui Liu, James M. Harris, Andrea Magri, Thomas Michler, Xiaodong Zhuang, Helene Borrmann, Rosalba Minisini, Nicholas R. Frampton, Jochen M. Wettengel, Laurent Mailly, Valentina D'Arienzo, Tobias Riedl, Luis Nobre, Michael P. Weekes, Mario Pirisi, Mathias Heikenwalder, Thomas F. Baumert, Ester M. Hammond, David R. Mole, Ulrike Protzer, Peter Balfe, Jane A. McKeating
Summary: HIFs play a crucial role in regulating HBV replication, revealing an evolutionary mechanism by which HBV exploits the HIF signaling pathway to persist in the low oxygen environment of the liver.
JOURNAL OF HEPATOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Thuy-Hang Nguyen, Stephanie Conotte, Alexandra Belayew, Anne-Emilie Decleves, Alexandre Legrand, Alexandra Tassin
Summary: Muscular dystrophies are genetic degenerative muscle disorders characterized by muscle wasting, often accompanied by respiratory impairments and hypoxemia. Hypoxic stress activates compensatory mechanisms, with HIF-1α playing a key role. Alterations in HIF-1α in muscle may impact the pathophysiology of muscular dystrophies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Jie-Ning Li, Pai-Sheng Chen, Ching-Feng Chiu, Yu-Jhen Lyu, Chiao Lo, Li-Wei Tsai, Ming-Yang Wang
Summary: This study reveals the regulatory role of TARBP2 in the ubiquitination-proteasomal degradation of HIF-1 alpha protein in breast cancer, showing its significance in cancer progression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Ilana R. Bernstein, Brett Nixon, Jess M. Lyons, Katerina B. Damyanova, Camila S. De Oliveira, Nishani S. Mabotuwana, Simone J. Stanger, Gerard E. Kaiko, Tan Hui Ying, Jon M. Oatley, Nicole M. Skillen, Alyssa J. Lochrin, Jera L. Peters, Tessa Lord
Summary: This study explores the role of hypoxia and the hypoxia-inducible transcription factor EPAS1 in regulating spermatogonial stem cell function in the mouse testis. The findings demonstrate that SSCs reside in hypoxic microenvironments and that EPAS1 is essential for robust SSC function in regenerative conditions. These findings shed light on the relationship between hypoxia and male fertility and may facilitate optimization of in vitro culture conditions for infertility treatment using SSCs, particularly for pediatric cancer survivors.
Review
Cell Biology
Lovis Kling, Adrian Schreiber, Kai-Uwe Eckardt, Ralph Kettritz
Summary: Hypoxia affects myeloid cells, while HIFs play a crucial role in modulating myeloid cell functions to adapt to low oxygen environments. HIF-1α and HIF-2α are key players in the innate immune response, though with different impact mechanisms.
JOURNAL OF LEUKOCYTE BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Seiya Yamada, Ayaka Sato, Naotada Ishihara, Hiroki Akiyama, Shin-ichi Sakakibara
Summary: The development of the brain requires a dynamic balance of SUMOylation/deSUMOylation to control neuronal polarization and migration, with the impact of Drp1 on mitochondrial morphology and endoplasmic reticulum controlled by Senp5L/5S competitively.
Article
Cell Biology
Rostislav Novak, Yamen Abu Ahmad, Michael Timaner, Eliya Bitman-Lotan, Avital Oknin-Vaisman, Roi Horwitz, Oliver Hartmann, Michaela Reissland, Viktoria Buck, Mathias Rosenfeldt, David Nikomarov, Markus Elmar Diefenbacher, Yuval Shaked, Amir Orian
Summary: This study reveals that the RNF4-BMP6-RGMb axis plays a crucial role in the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) and is also involved in tumorigenesis.
CELL DEATH & DISEASE
(2022)
Review
Endocrinology & Metabolism
Rodrigo A. Toledo, Camilo Jimenez, Gustavo Armaiz-Pena, Carlota Arenillas, Jaume Capdevila, Patricia L. M. Dahia
Summary: The HIF2 alpha inhibitor belzutifan has been approved by the FDA as a treatment for certain tumors, opening up a new approach in cancer therapy. This article reviews the molecular rationale and clinical data for HIF2 alpha blockade, as well as discussing potential mutations that may be sensitive to this approach. Resistance mechanisms to HIF2 alpha inhibitors, including acquired mutations in HIF2 alpha and its interacting partner ARNT, are also outlined. The high efficacy of belzutifan in tumors driven by genetic hypoxia suggests that other mutations leading to HIF2 alpha stabilization should be further investigated.
Article
Oncology
Jessie S. Kroonen, Alwine B. Kruisselbrink, Inge H. Briaire-de Bruijn, Olaejirinde O. Olaofe, Judith V. M. G. Bovee, Alfred C. O. Vertegaal
Summary: The study found that SUMO expression levels correlate with the aggressiveness and disease outcome of chondrosarcoma, making SUMO a potential biomarker. Inhibition of SUMOylation showed promising effects on reducing chondrosarcoma growth, indicating SUMO as a potential therapeutic target.
Article
Cell Biology
Immacolata Giordano, Lucia Pirone, Veronica Muratore, Eukene Landaluze, Coralia Perez, Valerie Lang, Elisa Garde-Lapido, Monika Gonzalez-Lopez, Orhi Barroso-Gomila, Alfred C. O. Vertegaal, Ana M. Aransay, Jose Antonio Rodriguez, Manuel S. Rodriguez, James D. Sutherland, Rosa Barrio
Summary: The study investigates the interaction between two key transcription factors, CBX4 and SALL1, and reveals that increased SALL1 expression reduces the ubiquitination of CBX4, enhancing its stability. This leads to an increase in the number and size of CBX4-containing Polycomb bodies, resulting in greater repression of CBX4 target genes.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Gastroenterology & Hepatology
Sumit Kumar, Mark J. A. Schoonderwoerd, Jessie S. Kroonen, Ilona J. de Graaf, Marjolein Sluijter, Dina Ruano, Roman Gonzalez-Prieto, Matty Verlaan-de Vries, Jasper Rip, Ramon Arens, Noel F. C. C. de Miranda, Lukas J. A. C. Hawinkels, Thorbald van Hall, Alfred C. O. Vertegaal
Summary: The pharmacological inhibition of the SUMO pathway represents a potential strategy for targeting PDAC by inhibiting cancer cell cycle progression and activating anti-tumor immunity through interferon signaling. TAK-981, a novel small molecule inhibitor, has shown potential in reducing SUMOylation and inhibiting the proliferation of PDAC cells.
Review
Cell Biology
Fredrik Trulsson, Alfred C. O. Vertegaal
Summary: This review discusses the biological importance of site-specific modifications by ubiquitin and SUMO in regulating the DNA damage response, protein quality control, and cell cycle progression. The review also explores the machinery responsible for these modifications and methods to identify ubiquitin and SUMO modified sites. The authors emphasize the need for further innovation in the field to address challenges and long-standing questions.
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Orhi Barroso-Gomila, Fredrik Trulsson, Veronica Muratore, Inigo Canosa, Laura Merino-Cacho, Ana Rosa Cortazar, Coralia Perez, Mikel Azkargorta, Ibon Iloro, Arkaitz Carracedo, Ana M. Aransay, Felix Elortza, Ugo Mayor, Alfred C. O. Vertegaal, Rosa Barrio, James D. Sutherland
Summary: SUMO-ID technology combines TurboID proximity biotinylation and protein-fragment complementation to study SUMO-dependent interactions, providing insight into the complexity of the ubiquitin code.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Fredrik Trulsson, Vyacheslav Akimov, Mihaela Robu, Nila van Overbeek, David Aureliano Perez Berrocal, Rashmi G. Shah, Juergen Cox, Girish M. Shah, Blagoy Blagoev, Alfred C. O. Vertegaal
Summary: This study compares the regulatory effects of the proteasome and deubiquitinating enzymes (DUBs) on the ubiquitinated proteome. The authors find preferential sets of substrates regulated by DUBs or by the proteasome. Moreover, they find that PARP1 is hyper-ubiquitinated in response to DUB inhibition, which increases its enzymatic activity.
NATURE COMMUNICATIONS
(2022)
Review
Cell Biology
Alfred C. O. Vertegaal
Summary: Sumoylation is an essential post-translational modification that regulates many nuclear processes. Recent studies have revealed its roles in liquid-liquid phase separation, immunity, pluripotency, and disease, offering new therapeutic opportunities.
NATURE REVIEWS MOLECULAR CELL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Juliette A. Kamp, Bennie B. L. G. Lemmens, Ron J. Romeijn, Roman Gonzalez-Prieto, Jesper Olsen, Alfred C. O. Vertegaal, Robin van Schendel, Marcel Tijsterman
Summary: This study uncovers the crosstalk between RNA surveillance and DNA repair in living animals, revealing the role of SMG-1 in this process through genetic screens and genome-wide analyses. The findings shed light on how defects in RNA processing can affect DNA repair, and highlight the importance of SMG-1 in regulating this interaction.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Multidisciplinary Sciences
Charlotte Blessing, Katja Apelt, Diana van den Heuvel, Claudia Gonzalez-Leal, Magdalena B. Rother, Melanie van der Woude, Roman Gonzalez-Prieto, Adi Yifrach, Avital Parnas, Rashmi G. Shah, Tia Tyrsett Kuo, Daphne E. C. Boer, Jin Cai, Angela Kragten, Hyun-Suk Kim, Orlando D. Scharer, Alfred C. O. Vertegaal, Girish M. Shah, Sheera Adar, Hannes Lans, Haico van Attikum, Andreas G. Ladurner, Martijn S. Luijsterburg
Summary: Cells employ global genome nucleotide excision repair to repair a broad spectrum of genomic DNA lesions. Here, the authors reveal how chromatin is primed for repair, providing insight into mechanisms of chromatin plasticity during DNA repair.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Sarah Tessier, Omar Ferhi, Marie-Claude Geoffroy, Roman Gonzalez-Prieto, Antoine Canat, Samuel Quentin, Marika Pla, Michiko Niwa-Kawakita, Pierre Bercier, Domitille Rerolle, Pierre Therizols, Emmanuelle Fabre, Alfred C. O. Vertegaal, Hugues de The, Valerie Lallemand-Breitenbach
Summary: The authors identify novel PML partners and demonstrate their role in controlling sumoylation and maintaining the transcriptome and transposable element silencing in embryonic stem cells. These findings shed light on the functions of membrane-less organelles and provide new insights into the potential role of PML in embryonic stem cells and cancer.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Yara Huppelschoten, Rishov Mukhopadhyay, Jens Buchardt, Thomas E. E. Nielsen, Alfred C. O. Vertegaal, Huib Ovaa, Gerbrand J. van Der Heden J. van Noort
Summary: Researchers synthesized a large number of SUMO-based fluorescence polarization reagents to study enzyme preferences. Screening of five SENPs revealed differences in deconjugation activity and substrate preferences. The findings provide important evidence for understanding the mechanism of SENP-specific binding to SUMO.
Correction
Multidisciplinary Sciences
Sarah Tessier, Omar Ferhi, Marie-Claude Geoffroy, Roman Gonzalez-Prieto, Antoine Canat, Samuel Quentin, Marika Pla, Michiko Niwa-Kawakita, Pierre Bercier, Domitille Rerolle, Marilyn Tirard, Pierre Therizols, Emmanuelle Fabre, Alfred C. O. Vertegaal, Hugues de The, Valerie Lallemand-Breitenbach
NATURE COMMUNICATIONS
(2023)
Article
Cell Biology
Bharath Sampadi, Sylvia Vermeulen, Branislav Misovic, Jan J. J. Boei, Tanveer S. S. Batth, Jer-Gung Chang, Michelle T. T. Paulsen, Brian Magnuson, Joost Schimmel, Hanneke Kool, Cyriel S. S. Olie, Bart Everts, Alfred C. O. Vertegaal, Jesper V. V. Olsen, Mats Ljungman, Penny A. A. Jeggo, Leon H. F. Mullenders, Harry Vrieling
Summary: In this study, using temporal multi-omic systems analyses, it was found that the DNA damage response (DDR) displayed dose proportionality, but many other molecular and cellular responses did not. Additionally, a novel mode of phospho-signaling and large-scale dephosphorylation events that regulate mitotic exit control and the G2/M checkpoint were uncovered. Furthermore, after low dose radiation exposure, reactive oxygen species and antioxidant defense were prominently activated, while DDR genes were prominently activated after high dose radiation.
Article
Oncology
Jessie S. Kroonen, Ilona J. de Graaf, Sumit Kumar, Dennis F. G. Remst, Anne K. Wouters, Mirjam H. M. Heemskerk, Alfred C. O. Vertegaal
Summary: Combination therapies using SUMO inhibition and DNA hypomethylation can effectively reduce cell proliferation in MYC-driven hematopoietic malignancies. In vivo experiments also showed promising results in reducing tumor growth with the combined treatment. Tailored combination therapies based on molecular mechanisms have the potential to improve cancer treatment efficacy.
Article
Multidisciplinary Sciences
Laura A. Claessens, Matty Verlaan-de Vries, Ilona J. de Graaf, Alfred C. O. Vertegaal
Summary: The SUMO protease SENP6 plays a crucial role in maintaining genomic stability by disassembling SUMO2/3 polymers from DNA damage response proteins, preventing their trapping at sites of DNA damage and nuclear condensates.
NATURE COMMUNICATIONS
(2023)