Article
Multidisciplinary Sciences
Chun-Yi Cho, Charles A. Seller, Patrick H. O'Farrell
Summary: During the S phase in metazoans, the replication of different parts of the genome is coordinated in a temporal program. The mechanism controlling the timing and coordination of origin firing is not fully understood. In this study, researchers found that Rif1, an inhibitor of DNA replication, recruits PP1 and counteracts the firing of origins by S-phase kinases. They also discovered that the activity level of the S-phase kinase DDK affects the dispersal of Rif1 hubs, and that the recruited PP1 retards this dispersal. This study proposes a model in which the spatial and temporal coordination of late replication in the mid-blastula transition (MBT) embryo is controlled by self-stabilizing Rif1-PP1 hubs.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biology
Mark C. Johnson, Geylani Can, Miguel Monteiro Santos, Diana Alexander, Philip Zegerman
Summary: This study reveals that Rad53 phosphorylates the same substrates throughout the cell cycle, not just in S-phase, suggesting its roles beyond S-phase. By inhibiting 51d3 and Dbf4, Rad53 limits re-replication in G2/M, preventing gene amplification, and inhibiting these substrates in G1 prevents premature initiation at the G1/S transition. This redefinition of the 'S-phase checkpoint' has implications for understanding checkpoint function in cancers without proper cell cycle controls.
Article
Multidisciplinary Sciences
Pedro Ferreira, Verena Hoefer, Nora Kronshage, Anika Marko, Karl-Uwe Reusswig, Bilal Tetik, Christoph Diessel, Kerstin Koehler, Nikolai Tschernoster, Janine Altmueller, Nina Schulze, Boris Pfander, Dominik Boos
Summary: In metazoan cells, MTBP is phosphorylated by at least three kinase pathways, including cell cycle CDK and Cdk8/19-cyclin C. Phospho-mimetic mutations can promote origin firing, while phosphorylation at DNA damage checkpoint kinase sites inhibits this capability. MTBP acts as a regulation platform for origin firing in metazoan cells.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Alex J. Whale, Michelle King, Ryan M. Hull, Felix Krueger, Jonathan Houseley
Summary: Adaptive mutations can cause drug resistance and increase tolerance to chemical treatment. The study investigates the transcription mechanism of the copper resistance gene CUP1 in budding yeast and its impact on copy number variation. The results demonstrate that CUP1 transcription requires TREX-2 and Mediator, and that replication stress and homologous recombination contribute to the amplification of CUP1 gene. The study also highlights the critical role of late-firing replication origins in CUP1 amplification.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Yue Wang, Yunchao Huang, Edith Cheng, Xinhua Liu, Yu Zhang, Jianguo Yang, Jordan T. F. Young, Grant W. Brown, Xiaohan Yang, Yongfeng Shang
Summary: This study reveals an unexpected role for lysine-specific demethylase 1 (LSD1) in euchromatic origin firing and replication timing, highlighting the importance of epigenetic regulation in the activation of replication origins. The findings support the potential use of selective inhibitors of LSD1 in cancer therapy, while emphasizing the need to maintain an appropriate level of LSD1 to minimize side effects.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2022)
Review
Biology
Eman Zaffar, Pedro Ferreira, Luis Sanchez-Pulido, Dominik Boos
Summary: The initiation of DNA replication is a crucial step for the accurate inheritance of genetic information. Recent studies have revealed important insights into the molecular processes and cellular regulation of replication initiation in eukaryotic cells, with the identification of the MTBP protein as a key factor. MTBP plays a critical role in the initiation of replication and is regulated by kinases and controlled degradation.
Article
Biochemistry & Molecular Biology
Fiona Jenkinson, Kang Wei Tan, Barbara Schopf, Miguel M. Santos, Philip Zegerman
Summary: In eukaryotes, cyclin-dependent kinase (CDK) inhibits helicase loading factors to ensure the exact duplication of the genome. CDK activates origin firing by phosphorylating Sld2 and Sld3, forming a transient intermediate called the pre-initiation complex (pre-IC). In yeast, the CDK phosphorylations of Sld3 and Sld2 are rapidly turned over by the phosphatases PP2A and PP4 during S phase. This dephosphorylation is important for genome-wide origin firing, pre-IC formation, and maintaining Sld3 dephosphorylation in G1 phase. PP2ARts1 specifically targets Sld3 and its dephosphorylation is critical for replication and cell viability.
Article
Biology
Olivier Haccard, Diletta Ciardo, Hemalatha Narrissamprakash, Odile Bronchain, Akiko Kumagai, William G. Dunphy, Arach Goldar, Kathrin Marheineke
Summary: In early Xenopus embryonic cycles, Rif1 restrains the replication program globally. Depletion of Rif1 leads to an accelerated temporal program and increased chromatin recruitment of key initiation factors. The absence of Rif1 compresses the temporal program towards more homogeneity and increases the availability of limiting initiation factors.
COMMUNICATIONS BIOLOGY
(2023)
Review
Cell Biology
Rafaela Fagundes, Leonardo K. Teixeira
Summary: DNA replication must be precisely controlled, and cell cycle transitions are regulated by the Cyclin-Dependent Kinases (CDKs) family. The Cyclin E/CDK2 complex controls cell cycle progression and DNA replication through phosphorylation of specific substrates in normal cycles, while its oncogenic activation causes replication stress and genomic instability.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Cell Biology
Nicolas Boehly, Ann-Kathrin Schmidt, Xiaoxiao Zhang, Benjamin O. Slusarenko, Magdalena Hennecke, Maik Kschischo, Holger Bastians
Summary: Replication stress-induced increased origin firing can trigger chromosomal instability in human cancer cells, which is associated with W-CIN in human cancer specimens.
Article
Biochemistry & Molecular Biology
Liu Mei, Katarzyna M. Kedziora, Eun-Ah Song, Jeremy E. Purvis, Jeanette Gowen Cook
Summary: In this study, the authors quantified the dynamics and distribution of DNA replication origin licensing for the first time. They found that the loading rate of MCM complexes is different between euchromatin and heterochromatin. The study also revealed the consequences of heterochromatin licensing dynamics, leading to DNA damage accumulation in subsequent phases. Therefore, the length of G1 phase is critical for sufficient MCM loading, genome duplication, and genome stability.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biology
Pedro Ferreira, Luis Sanchez-Pulido, Anika Marko, Chris P. Ponting, Dominik Boos
Summary: The faithful duplication of the genome requires controlled replication origin firing. The proteins Treslin/TICRR and its yeast counterpart Sld3 play a crucial role in regulating the firing of replication origins. A revised domain architecture model of Treslin/TICRR is proposed, revealing a conserved beta-barrel fold in the middle domain (M domain) shared by Treslin/TICRR and Sld3. It is found that Treslin/Sld3 and MTBP/Sld7 engage in homotypic interactions similar to the dimerization of Ku70-Ku80. Mutants of the Treslin/TICRR domain indicate the importance of all Sld3-core domains and the non-conserved terminal domains during origin firing in human cells.
LIFE SCIENCE ALLIANCE
(2022)
Review
Biology
Seiji Tanaka, Shiho Ogawa
Summary: The activity of replication origins is regulated by firing factors, and dimerization of these factors may contribute to the simultaneous activation of two sets of helicases and thus the efficient assembly of bidirectional replication forks.
Article
Genetics & Heredity
Diletta Ciardo, Olivier Haccard, Hemalatha Narassimprakash, Jean-Michel Arbona, Olivier Hyrien, Benjamin Audit, Kathrin Marheineke, Arach Goldar
Summary: During cell division, origin firing requires interaction with potential origins. Regions with high probability of origin firing may escape intra-S checkpoint regulation, and variability in DNA synthesis rate near replication forks also influences replication origin firing dynamics.
Article
Multidisciplinary Sciences
Shivang Hina-Nilesh Joshi, Chentao Yong, Andras Gyorgy
Summary: The ability to externally control gene expression has been important for all areas of biological research, especially for synthetic biology. Here the authors present plasmid TULIP which offers DNA copy number control via chemical induction to accelerate the design, prototyping, and reuse of gene circuits in diverse contexts.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Priyanka Singh, Krishnananda Samanta, Ndeye Mathy Kebe, Gregory Michel, Baptiste Legrand, Vera E. Sitnikova, Andrey Kajava, Michel Pages, Patrick Bastien, Christelle Pomares, Olivier Coux, Jean-Francois Hernandez
Summary: Developing less toxic and more efficient treatments for leishmaniases and trypanosomiases is urgent. By targeting the parasite mitochondrial HslVU protease, which is essential for growth and has no analogue in the human host, we have developed compounds potentially inhibiting the complex assembly. Through the study of the structure-activity relationships, we have obtained more potent analogues. Additionally, conjugates of the analogues and a mitochondrial penetrating peptide have been found to penetrate into the parasite and inhibit its growth without toxicity to human cells.
BIOORGANIC CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Jean-Yves Alejandro Frayssinhes, Fulvia Cerruti, Justine Laulin, Angela Cattaneo, Angela Bachi, Sebastien Apcher, Olivier Coux, Paolo Cascio
Summary: PA28 gamma is a nuclear activator of the 20S proteasome, stimulating the degradation of unfolded proteins; it increases breakdown rates of these proteins by 20S proteasomes while decreasing the variability of peptides potentially suitable for MHC class I antigen presentation.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Hematology
Rosa Paolillo, Mathias Boulanger, Pierre Gatel, Ludovic Gabellier, Marion De Toledo, Denis Tempe, Rawan Hallal, Dana Akl, Jerome Moreaux, Hayeon Baik, Elise Gueret, Christian Recher, Jean-Emmanuel Sarry, Guillaume Cartron, Marc Piechaczyk, Guillaume Bossis
Summary: Resistance to chemotherapeutic drugs is a major cause of treatment failure in acute myeloid leukemias (AML). This study found that upregulation of NOX2 NADPH oxidase subunit genes is associated with increased reactive oxygen species production and resistance to daunorubicin in AML cells. High expression of these genes is also a marker of adverse prognosis in AML patients.
Article
Chemistry, Multidisciplinary
Alexis Fayd'herbe De Maudave, Wilhem Leconet, Karine Toupet, Michael Constantinides, Guillaume Bossis, Marion de Toledo, Jerome Vialaret, Christophe Hirtz, Adolfo Lopez-Noriega, Christian Jorgensen, Daniele Noel, Pascale Louis-Plence, Sylvestre Grizot, Martin Villalba
Summary: Monoclonal antibodies have high therapeutic potential for cancer or autoimmune diseases, but intravenous administration can lead to off-target effects. Utilizing a local controlled-delivery approach with in situ forming depot technology can help address this issue.
JOURNAL OF CONTROLLED RELEASE
(2022)
Article
Genetics & Heredity
Cecile Ribot, Cedric Soler, Aymeric Chartier, Sandy Al Hayek, Rima Nait-Saidi, Nicolas Barbezier, Olivier Coux, Martine Simonelig
Summary: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. Previous studies have shown that the ubiquitin-proteasome system (UPS) is deregulated in OPMD, contributing to the disease pathogenesis. In this Drosophila model of OPMD, increased UPS activity leads to muscle protein degradation and atrophy. Inhibitors of proteasome activity, such as MG132, show potential as a pharmacological approach for OPMD treatment, improving muscle function. This study highlights the importance of UPS deregulation in OPMD and suggests proteasome inhibitors as potential therapeutic options.
Article
Oncology
Gregoire Quinet, Wendy Xolalpa, Diana Reyes-Garau, Nuria Profitos-Peleja, Mikel Azkargorta, Laurie Ceccato, Maria Gonzalez-Santamarta, Maria Marsal, Jordi Andilla, Fabienne Aillet, Francesc Bosch, Felix Elortza, Pablo Loza-Alvarez, Brigitte Sola, Olivier Coux, Rune Matthiesen, Gael Roue, Manuel S. Rodriguez
Summary: The research identified an enrichment of autophagy-lysosome system (ALS) components in bortezomib (BTZ)-resistant cells in mantle cell lymphoma (MCL) patients. By blocking proteaphagy, the normal proteasomal activity was reactivated and the BTZ antitumor effect was restored in vitro and in vivo models of BTZ resistance. These findings suggest a proteolytic switch from the ubiquitin-proteasome system (UPS) to ALS in B-cell lymphoma refractory to proteasome inhibition, opening up new therapeutic avenues for treatment-resistant tumors.
Review
Pharmacology & Pharmacy
Anaelle Bailly, Ollivier Milhavet, Jean-Marc Lemaitre
Summary: Cell reprogramming techniques, including RNA-based strategies, have shown great potential in treating various diseases and improving healthspan and longevity.
Article
Biochemistry & Molecular Biology
Meenakshi Basu Shrivastava, Barbara Mojsa, Stephan Mora, Ian Robbins, Guillaume Bossis, Irena Lassot, Solange Desagher
Summary: NFATc3, a member of the NFAT family of transcription factors, plays a critical role in neuronal apoptosis. This study identifies Trim39 as an E3 ubiquitin-ligase that regulates the stability and activity of NFATc3 by binding and ubiquitinating it. Trim17 is found to inhibit Trim39-mediated ubiquitination of NFATc3 by reducing the E3 ligase activity and interaction between Trim39 and NFATc3. Additionally, Trim39 is identified as a new SUMO-targeted E3 ubiquitin-ligase. These findings demonstrate the role of Trim39 as a STUbL for NFATc3 in modulating neuronal apoptosis.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Cell Biology
Pharvendra Kumar, Amarendranath Soory, Salman Ahmad Mustfa, Dipanka Tanu Sarmah, Himadri Devvanshi, Samrat Chatterjee, Guillaume Bossis, Girish S. Ratnaparkhi, Chittur Srikanth
Summary: This study investigated the regulation of SUMO pathway genes during Salmonella Typhimurium (STm) infection. It was found that c-Fos, a component of AP-1, directly binds to the promoters of UBC9 and PIAS1 to regulate their expression. Perturbation of c-Fos causes changes in the expression of UBC9 and PIAS1, and SUMOylation-deficient c-Fos leads to uncontrolled activation of target genes, favoring STm replication.
JOURNAL OF CELL SCIENCE
(2022)
Article
Multidisciplinary Sciences
Moira Rossitto, Stephanie Dejardin, Chris M. Rands, Stephanie Le Gras, Roberta Migale, Mahmoud-Reza Rafiee, Yasmine Neirijnck, Alain Pruvost, Anvi Laetitia Nguyen, Guillaume Bossis, Florence Cammas, Lionel Le Gallic, Dagmar Wilhelm, Robin Lovell-Badge, Brigitte Boizet-Bonhoure, Serge Nef, Francis Poulat
Summary: Gonadal fate in mammals is determined during embryogenesis and is actively maintained in adulthood. This study shows that E3-SUMO ligase activity of TRIM28 is required for ovarian identity maintenance and testicular-specific gene repression in mouse adult ovary; in its absence, ovarian granulosa cells transdifferentiate to Sertoli cells.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Damien Dufour, Typhanie Dumontet, Isabelle Sahut-Barnola, Aude Carusi, Meline Onzon, Eric Pussard, James Jr Wilmouth, Julie Olabe, Cecily Lucas, Adrien Levasseur, Christelle Damon-Soubeyrand, Jean-Christophe Pointud, Florence Roucher-Boulez, Igor Tauveron, Guillaume Bossis, Edward T. Yeh, David T. Breault, Pierre Val, Anne-Marie Lefrancois-Martinez, Antoine Martinez
Summary: SUMOylation is a dynamic posttranslational modification that plays a critical role in adrenal homeostasis and stress responsiveness. Disruption of SENP2 activity in steroidogenic cells leads to specific hypoplasia of the zona fasciculata, a blunted response to ACTH, and isolated glucocorticoid deficiency. The mechanism involves a shift in the balance between ACTH/PKA and WNT/beta-catenin signaling, resulting in repression of PKA activity and ectopic activation of beta-catenin.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Mathias Boulanger, Mays Aqrouq, Denis Tempe, Chamseddine Kifagi, Marko Ristic, Dana Akl, Rawan Hallal, Aude Carusi, Ludovic Gabellier, Marion de Toledo, Jon-Otti Sigurdsson, Tony Kaoma, Charlotte Andrieu-Soler, Thierry Forne, Eric Soler, Yosr Hicheri, Elise Gueret, Laurent Vallar, Jesper Olsen, Guillaume Cartron, Marc Piechaczyk, Guillaume Bossis
Summary: Daunorubicin (DNR), a main drug used for treating Acute Myeloid Leukemia (AML), induces rapid and broad transcriptional changes in AML cells within 3 hours. These changes involve genes controlling cell proliferation, death, inflammation, and immunity. DNR also causes deSUMOylation of chromatin proteins, primarily transcription factors, co-regulators, and chromatin organizers, and this deSUMOylation is crucial for the transcriptional reprogramming. Inhibition of SUMOylation with ML-792 prevents the chromatin loop reconfiguration and interaction between CTCF and SUMO-bound NFKB2 promoter.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Giuseppe Fusi, Michael Constantinides, Christina Fissoun, Lydiane Pichard, Yves-Marie Pers, Rosanna Ferreira-Lopez, Veronique Pantesco, Christophe Poulet, Olivier Malaise, Dominique De Seny, Jean-Marc Lemaitre, Christian Jorgensen, Jean-Marc Brondello
Summary: Senescent cells play a role in tissue degeneration and contribute to age-related diseases such as osteoarthritis. This study investigates how the senescence-driven microenvironment affects the fate of MSCs and contributes to the progression of osteoarthritis.
Article
Chemistry, Multidisciplinary
Robert D. Healey, Essa M. Saied, Xiaojing Cong, Gergely Karsai, Ludovic Gabellier, Julie Saint-Paul, Elise Del Nero, Sylvain Jeannot, Marion Drapeau, Simon Fontanel, Damien Maurel, Shibom Basu, Cedric Leyrat, Jerome Golebiowski, Guillaume Bossis, Cherine Bechara, Thorsten Hornemann, Christoph Arenz, Sebastien Granier
Summary: Sphingolipid metabolism is tightly regulated by enzymes, with recent attention on the discovery and mechanism of action of the first drug-like inhibitors of alkaline ceramidase 3 (ACER3). This discovery opens up a new paradigm for targeting ACER3 in drug discovery efforts.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Robert D. Healey, Essa M. Saied, Xiaojing Cong, Gergely Karsai, Ludovic Gabellier, Julie Saint-Paul, Elise Del Nero, Sylvain Jeannot, Marion Drapeau, Simon Fontanel, Damien Maurel, Shibom Basu, Cedric Leyrat, Jerome Golebiowski, Guillaume Bossis, Cherine Bechara, Thorsten Hornemann, Christoph Arenz, Sebastien Granier
Summary: This study presents the discovery and mechanism of action of the first drug-like inhibitors of alkaline ceramidase 3 (ACER3), as well as the characterization of enzyme:inhibitor interactions using mass spectrometry and MD simulations. The use of novel fluorescent ceramide substrates enables screening of large compound libraries, offering a new paradigm for inhibition of lipid metabolizing enzymes with non-lipidic small molecules. The findings lay the groundwork for targeting ACER3 in drug discovery efforts.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
