Article
Biochemistry & Molecular Biology
Michael Taschner, Jerome Basquin, Barbara Steigenberger, Ingmar B. Schaefer, Young-Min Soh, Claire Basquin, Esben Lorentzen, Markus Raeschle, Richard A. Scheltema, Stephan Gruber
Summary: The Nse5/6 sub-complex inhibits the Smc5/6 ATPase by preventing productive ATP binding, which is relieved by plasmid DNA binding. This direct inhibition modulates DNA substrate selection.
Article
Multidisciplinary Sciences
Sumedha Agashe, Chinnu Rose Joseph, Teresa Anne Clarisse Reyes, Demis Menolfi, Michele Giannattasio, Anja Waizenegger, Barnabas Szakal, Dana Branzei
Summary: The study reveals that Smc5/6 acts together with Top3 within the STR complex to regulate the DNA processing activities of Sgs1 and Top3, maintaining genome structural integrity and mediating DNA replication completion.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Hanchen Chen, Chengpeng He, Chongyang Wang, Xuanpeng Wang, Fengyin Ruan, Junjie Yan, Ping Yin, Yingxiang Wang, Shunping Yan
Summary: This study revealed the function of RAD51 in meiosis and the inhibitory effect of SMC5/6 on DMC1 as a control mechanism during meiotic recombination.
Review
Biochemistry & Molecular Biology
Xiao P. Peng, Xiaolan Zhao
Summary: In this article, the authors discuss the composition, architecture, functions, and mechanisms of the SMC complex Smc5/6 in chromosomal replication and repair, as well as its involvement in disease. The importance of Smc5/6 for growth, genotoxin resistance, and host defense in plants and animals is highlighted. Recent advancements, including structural and single-molecule studies, have provided greater insights into the mechanisms underlying Smc5/6 functions. The integration of recent studies on Smc5/6 has identified emerging features of this unique SMC complex and explains its diverse cellular functions and roles in disease pathogenesis, while also pointing out key areas requiring further investigation.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Microbiology
Chunyan Han, Dun Zhang, Chenwu Gui, Liang Huang, Sijia Chang, Lianghui Dong, Lei Bai, Shuwen Wu, Ke Lan
Summary: A study finds that the cellular protein structural maintenance of chromosome (SMC) complex SMC5/6 can inhibit the replication of Kaposi's sarcoma-associated herpesvirus (KSHV) by condensing the viral chromatin and creating a repressive chromatin structure. In response, KSHV utilizes the viral protein RTA to degrade the SMC5/6 complex and counteract its inhibitory effect on viral gene transcription.
Article
Biochemistry & Molecular Biology
Stephen T. Hallett, Isabella Campbell Harry, Pascale Schellenberger, Lihong Zhou, Nora B. Cronin, Jonathan Baxter, Thomas J. Etheridge, Johanne M. Murray, Antony W. Oliver
Summary: The Smc5/6 complex plays a crucial role in recombination and virus replication prevention. The cryo-EM structure reveals the architectural overview of the complex and the binding of the Nse1/3/4 subcomplex to the SMC protein core. The interaction between Smc5 and Nse1 through the head domain is essential, and mutations in the Nse1 region result in growth defects and reduced chromatin association of the Smc5/6 complex.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biology
Martina Oravcova, Minghua Nie, Nicola Zilio, Shintaro Maeda, Yasaman Jami-Alahmadi, Eros Lazzerini-Denchi, James A. Wohlschlegel, Helle D. Ulrich, Takanori Otomo, Michael N. Boddy
Summary: This study identifies a novel SMC5/6 subunit called SIMC1 and elucidates its mechanism of localizing SMC5/6 to nuclear bodies through interacting domains.
Article
Multidisciplinary Sciences
Longfei Zhu, Nadia Fernandez-Jimenez, Maja Szymanska-Lejman, Alexandre Pele, Charles J. Underwood, Heidi Serra, Christophe Lambing, Julia Dluzewska, Tomasz Bieluszewski, Monica Pradillo, Ian R. Henderson, Piotr A. Ziolkowski
Summary: This study reveals the importance of the SMC5/6 complex in ensuring the proper progress of meiotic recombination in plants, showing the impact of SNI1 mutations and interactions with other genes on crossover distribution.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Cell Biology
Sarah Moradi-Fard, Aditya Mojumdar, Megan Chan, Troy A. A. Harkness, Jennifer A. Cobb
Summary: The ribosomal DNA (rDNA) in Saccharomyces cerevisiae is organized within the nucleolus by two important regions called intergenic spacer 1 (IGS1) and IGS2. The Smc5/6 complex plays a crucial role in rDNA stability beyond its known function in homologous recombination at the replication fork barrier (RFB) in IGS1. Fob1 and Sir2 are required for optimal binding of Smc5/6 at IGS1 and IGS2 respectively, and their interdependent interactions contribute to nucleolar compaction and transcriptional silencing of rDNA.
Article
Cell Biology
Xue Bessie Su, Menglu Wang, Claudia Schaffner, Olga O. Nerusheva, Dean Clift, Christos Spanos, David A. Kelly, Michael Tatham, Andreas Wallek, Yehui Wu, Juri Rappsilber, A. Arockia Jeyaprakash, Zuzana Storchova, Ronald T. Hay, Adele L. Marston
Summary: During cell mitosis, SUMOylation plays a critical role in modulating error correction mechanisms by regulating protein interactions, leading to stable sister kinetochore biorientation and timely anaphase onset.
JOURNAL OF CELL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Stephen R. Wellard, Yujiao Zhang, Chris Shults, Xueqi Zhao, Matthew McKay, Stephen A. Murray, Philip W. Jordan
Summary: The study highlights the critical role of centriole duplication, centrosome maturation, and separation in establishing bipolar spindles during meiotic divisions. The findings show that Polo-like kinase 1 and Aurora A kinase are essential for centrosome maturation and separation, and PLK1 is required to inhibit the second round of centriole duplication until late anaphase I to ensure accurate chromosome segregation during spermatogenesis.
Article
Biochemistry & Molecular Biology
Aera Jo, Shibai Li, Jin Woo Shin, Xiaolan Zhao, Yunje Cho
Summary: The Nse1-Nse3-Nse4 subcomplex within the Smc5/6 complex plays multiple roles in chromosome replication and DNA break repair through DNA binding and regulating ATP-dependent activities. The crystal structure of the subcomplex reveals how Nse4 is forced into a Z-shaped conformation by Nse1-Nse3, providing insights into potential disease-causing mutations. DNA binding and mutational analyses show the importance of Nse4 in DNA interaction and cell viability, suggesting its critical role in the complex.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Cell Biology
Eva Ibars, Joan Codina-Fabra, Gemma Belli, Celia Casas, Marc Tarres, Roger Sole-Soler, Neus P. Lorite, Pilar Ximenez-Embun, Javier Munoz, Neus Colomina, Jordi Torres-Rosell
Summary: This study reveals the crucial role of Nse1 subunit in nuclear ubiquitination, which impacts the ubiquitination of proteins involved in ribosome biogenesis and metabolism. The study also suggests a connection between Nse1 and RNA polymerase I (RNA Pol I) ubiquitination. The findings provide insights into the important functions of Nse1 and its association with ribosome biogenesis and RNA Pol I.
Article
Biology
Tsan-Tzu Yang, Ming-Feng Chiang, Che-Chang Chang, Shii-Yi Yang, Shih-Wen Huang, Nan-Shih Liao, Hsiu-Ming Shih, Wei Hsu, Kuo- Lin
Summary: SENP2 is involved in regulating post-translational modification of Smad4 in Th17 cells and intestinal bowel diseases. Lack of Senp2 exacerbates the severity of experimental colitis and leads to elevated levels of pathogenic Th17 cells and dysbiosis of the intestinal microbiome. SENP2 enzymatic activity is important for deSUMOylation of Smad4 and regulates the pathogenicity of Th17 cells.
COMMUNICATIONS BIOLOGY
(2023)
Review
Microbiology
Christos Gogou, Aleksandre Japaridze, Cees Dekker
Summary: The process of DNA segregation in bacteria involves various mechanisms such as pushing and pulling, while some bacteria rely on entropic forces for chromosome de-mixing. Understanding these mechanisms is crucial for genome segregation research.
FRONTIERS IN MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Monica M. Franca, Yazmine B. Condezo, Maeva Elzaiat, Natalia Felipe-Medina, Fernando Sanchez-Saez, Sergio Munoz, Raquel Sainz-Urruela, M. Rosario Martin-Hervas, Rodrigo Garcia-Valiente, Manuel A. Sanchez-Martin, Aurora Astudillo, Juan Mendez, Elena Llano, Reiner A. Veitia, Berenice B. Mendonca, Alberto M. Pendas
Summary: A homozygous RAD51B variant was identified in sisters with POI, leading to DNA repair defects and reduced crossovers. This variant also affected RAD51B interactions and replication fork progression, indicating a role in somatic genome stability maintenance.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Biochemistry & Molecular Biology
Kurt Jacobs, Cyril Doerdelmann, Jana Krietsch, Daniel Gonzalez-Acosta, Nicolas Mathis, Saul Kushinsky, Estrella Guarino, Carmen Gomez-Escolar, Dolores Martinez, Jonas A. Schmid, Peter J. Leary, Raimundo Freire, Almudena R. Ramiro, Christine M. Eischen, Juan Mendez, Massimo Lopes
Summary: The mechanisms linking stem cell division to tumorigenesis are still not well understood. This study reveals that DNA damage associated with hematopoietic stem and progenitor cell proliferation induced by simulated viral infection is restricted to hematopoietic stem cells and these cells can rewire their DNA damage response. Further experiments demonstrate that fine-tuning the plasticity of replication forks is essential for supporting stem cell functionality during proliferation stimuli.
Editorial Material
Oncology
Matilde Murga, Oscar Fernandez-Capetillo
Summary: These are exciting times to be involved in biomedical research, especially in the field of cancer drug discovery. The transition from scientific hypothesis to testable therapy is faster than ever, aided by the emergence of new technologies. This thematic issue provides an overview of recent advances and challenges in cancer drug development, offering a broad and updated perspective for those interested in developing cancer therapies.
MOLECULAR ONCOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Alba Corman, Oleksandra Sirozh, Vanesa Lafarga, Oscar Fernandez-Capetillo
Summary: The nucleolus is where ribosome biogenesis takes place, which is one of the most resource-intensive processes in eukaryotic cells. It is highly responsive to growth signaling and nucleolar insults, collectively known as nucleolar stress. Nucleolar alterations are a prominent feature in various human diseases, including cancer and neurodegeneration, and are also associated with aging. There have been numerous efforts to develop compounds targeting different aspects of nucleolar activity. This article provides an overview of therapeutic opportunities and current therapies for targeting nucleoli in different pathologies.
TRENDS IN BIOCHEMICAL SCIENCES
(2023)
Article
Cell Biology
Arnau Ulsamer, Adrian Martinez-Limon, Sina Bader, Sara Rodriguez-Acebes, Raimundo Freire, Juan Mendez, Eulalia de Nadal, Francesc Posas
Summary: The stress-activated protein kinases (SAPKs) and their functional homologs, such as Mrc1 and Claspin, play a protective role in preventing DNA damage during S-phase in both yeast and mammals.
Article
Biochemistry & Molecular Biology
Valeria Colicchia, Maria Haggblad, Oleksandra Sirozh, Bartlomiej Porebski, Mirela Balan, Xuexin Li, Louise Lidemalm, Jordi Carreras-Puigvert, Daniela Huhn, Oscar Fernandez-Capetillo
Summary: The tetR-regulated system was used to construct a human osteosarcoma cell line for inducible expression of TDP-43. Chemical screening with FDA-approved drugs identified compounds that prevented TDP-43 toxicity, but further experiments showed that these compounds inhibited doxycycline-dependent TDP-43 expression. A CRISPR/Cas9 screen revealed epigenetic regulators as potential modifiers of TDP-43 toxicity. However, G9a inhibition or TRIM28 loss also prevented doxycycline-dependent TDP-43 expression.
Review
Biochemistry & Molecular Biology
Carlos Lopez-Otin, Maria A. Blasco, Linda Partridge, Manuel Serrano, Guido Kroemer
Summary: Aging is driven by hallmarks that manifest with age, accelerate aging when accentuated experimentally, and can be decelerated, stopped, or reversed with therapeutic interventions. The twelve proposed hallmarks of aging include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected with each other and with the recently proposed hallmarks of health.
Article
Biochemistry & Molecular Biology
Karolina Jodkowska, Vera Pancaldi, Maria Rigau, Ricardo Almeida, Jose M. Fernandez-Justel, Osvaldo Grana-Castro, Sara Rodriguez-Acebes, Miriam Rubio-Camarillo, Enrique Carrillo-de Santa Pau, David Pisano, Fatima Al-Shahrour, Alfonso Valencia, Maria Gomez, Juan Mendez
Summary: In this study, the authors analyzed the activity of origins in mouse embryonic stem cells and examined their response to replicative stress. They found that stressed origins were also active in a small fraction of cells during normal S phase, and stress increased their activation frequency. The study also identified that origin efficiency is proportional to the proximity to transcriptional start sites and the number of contacts established between origin-containing chromatin fragments.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Sergio Pineiro-Hermida, Giuseppe Bosso, Raul Sanchez-Vazquez, Paula Martinez, Maria A. Blasco
Summary: Non-small cell lung cancer (NSCLC) is a leading cause of cancer death, and tumor progression is influenced by the interaction between cancer cells and the tumor microenvironment. Increased copy number and mRNA expression of TERT, a catalytic subunit of telomerase, is associated with decreased survival in NSCLC patients. Targeting telomeres may be an effective therapeutic approach in NSCLC treatment.
CELL DEATH AND DIFFERENTIATION
(2023)
Article
Multidisciplinary Sciences
Maud Debaugnies, Sara Rodriguez-Acebes, Jeremy Blondeau, Marie-Astrid Parent, Manuel Zocco, Yura Song, Viviane de Maertelaer, Virginie Moers, Mathilde Latil, Christine Dubois, Katia Coulonval, Francis Impens, Delphi Van Haver, Sara Dufour, Akiyoshi Uemura, Panagiota A. Sotiropoulou, Juan Mendez, Cedric Blanpain
Summary: This study reveals that cancer cells undergoing EMT are highly resistant to various anti-cancer therapies. RHOJ, a small GTPase preferentially expressed in EMT cancer cells, controls resistance to therapy by enhancing the response to replicative stress and activating the DNA-damage response. RHOJ interacts with proteins that regulate nuclear actin, and inhibition of actin polymerization sensitizes EMT tumor cells to chemotherapy-induced cell death in a RHOJ-dependent manner.
Article
Cell Biology
Teresa Fuertes, Emigdio Alvarez-Corrales, Carmen Gomez-Escolar, Patricia Ubieto-Capella, Alvaro Serrano-Navarro, Antonio de Molina, Juan Mendez, Almudena R. Ramiro, Virginia G. de Yebenes
Summary: The therapeutic potential of miR-28, a tumor suppressor, was analyzed for DLBCL. It was found that combination therapy with miR-28 and ibrutinib enhanced the anti-tumor effects by impairing DNA replication. The downregulation of the miR-28-plus-ibrutinib gene signature was associated with better survival in ABC-DLBCL patients.
CELL DEATH & DISEASE
(2023)
Article
Cell Biology
Paula Martinez, Raul Sanchez-Vazquez, Arpita Saha, Maria S. Rodriguez-Duque, Sara Naranjo-Gonzalo, Joy S. Osorio-Chavez, Ana V. Villar-Ramos, Maria A. Blasco
Summary: The severity of COVID-19 increases with age, suggesting that organismal aging contributes to its fatality. Previous studies have shown that COVID-19 severity is correlated with shorter telomeres in patient's leukocytes. Lung injury is a prominent feature of acute SARS-CoV-2 infection, which can progress to lung fibrosis. In this study, we found that post-COVID-19 patients have shorter telomeres and increased lung fibrosis compared to age-matched controls with lung cancer, suggesting a link between short telomeres in ATII cells and long-term lung fibrosis in post-COVID-19 patients.