Article
Immunology
Iman Dalloul, Brice Laffleur, Zeinab Dalloul, Batoul Wehbi, Florence Jouan, Baptiste Brauge, Paco Derouault, Jeanne Moreau, Sven Kracker, Alain Fischer, Anne Durandy, Sandrine Le Noir, Michel Cogne
Summary: AID is a key regulator of immunoglobulin gene diversification in B-cells, but recent research has shown that under certain conditions, the absence of AID can also lead to gene diversification. The repair process in these cases involves an increased usage of microhomology-mediated repair.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Immunology
Miles B. Horton, HoChan Cheon, Ken R. Duffy, Daniel Brown, Shalin H. Naik, Carolina Alvarado, Joanna R. Groom, Susanne Heinzel, Philip D. Hodgkin
Summary: This study reveals that B lymphocytes generate plasma cells with diverse antibody isotypes, and their fate is regulated by discrete mechanisms. Founder cells have a major influence on clonal plasma-cell fate, while class switch recombination (CSR) shows variation within clones. The CSR patterns are determined by the independent all-or-none expression of activation-induced cytidine deaminase and IgH germline transcription.
Article
Multidisciplinary Sciences
Tianpeng Zhang, Yashpal Rawal, Haoyang Jiang, Youngho Kwon, Patrick Sung, Roger A. Greenberg
Summary: Break-induced telomere synthesis (BITS) is a RAD51-independent mechanism that contributes to alternative lengthening of telomeres. This process utilizes a minimal replisome comprising PCNA and DNA polymerase-d to perform conservative DNA repair synthesis over long stretches. The response of this repair synthesis to complex secondary DNA structures and whether additional DNA repair events are orchestrated by the break-induced replisome remain unclear. In this study, the telomeric DNA damage response proteome during BITS was captured using a combination of synchronous double-strand break induction and proteomics of isolated chromatin segments (PICh). The findings revealed a replication stress-dominant response, with repair synthesis-driven DNA damage tolerance signaling through RAD18-dependent PCNA ubiquitination. The SNM1A nuclease was identified as the major effector of ubiquitinated PCNA-dependent DNA damage tolerance, playing a critical role in resection-dependent lesion bypass in mammalian cells.
Article
Multidisciplinary Sciences
Donna R. Whelan, Eli Rothenberg
Summary: Using single-molecule localization super-resolution imaging assays, we observed the spatiotemporal behavior of key mediator and nuclease proteins during DNA resection at single-ended double-strand breaks. Multiple simultaneous resection events were demonstrated, with recruitment of various proteins and completion of resection 2 to 4 hours after break induction. Additionally, we identified potential roles of BRCA1 and BLM in homology search and repair resolution during HR.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biology
Hongchang Zhao, Stella R. Hartono, Kirtney Mae Flores de Vera, Zheyuan Yu, Krishni Satchi, Tracy Zhao, Roger Sciammas, Lionel Sanz, Frederic Chedin, Jacqueline Barlow, Michela Di Virgilio
Summary: Class switch recombination is a crucial process for generating distinct antibody isotypes, and defects in this process are associated with autoimmune disorders and lymphoma genesis. In this study, we found that cells lacking two enzymes involved in removing R loops exhibited increased R loop formation and genome instability at the immunoglobulin heavy chain locus. However, this did not affect transcriptional activity, AID recruitment, or class switch recombination efficiency. Our findings suggest that senataxin and RNase H2 act together in removing R loops, promoting efficient repair and suppressing AID-dependent genome instability and insertional mutagenesis.
Article
Cell Biology
Wanyu Bai, Guangchao Zhu, Jiejie Xu, Pingyue Chen, Feilong Meng, Hongman Xue, Chun Chen, Junchao Dong
Summary: The study reveals a critical role of the flap endonuclease XPF-ERCC1 in A-EJ and oncogenic translocation in mouse B cells during class switch recombination (CSR). XPF-ERCC1SLX4 complex helps in achieving CSR in B cells, while deficiency of DNA ligase 4 and XPF-ERCC1 leads to impaired class switching process. ERCC1 plays an important role in resolving 3' single-stranded DNA flaps.
Article
Cell Biology
Xikui Sun, Jingning Bai, Jiejie Xu, Xiaoli Xi, Mingyu Gu, Chengming Zhu, Hongman Xue, Chun Chen, Junchao Dong
Summary: The study demonstrates the critical roles of CtIP and Mre11 in mediating A-EJ CSR, while DNA2 and BLM are involved in long S region DSB resection. Additionally, ATM and its kinase activity can function partly independently of CtIP/Mre11 to mediate A-EJ switching.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Cell Biology
Ilaria Ceppi, Elda Cannavo, Helene Bret, Rosa Camarillo, Francesca Vivalda, Roshan Singh Thakur, Amador Romero-Franco, Alessandro A. Sartori, Pablo Huertas, Raphael Guerois, Petr Cejka
Summary: In this study, the researchers used AlphaFold2 to identify a separation-of-function mutant of CtIP, CtIP-F728E-Y736E, which can still work with MRN but cannot stimulate ssDNA degradation by DNA2. The findings support a model in which the phosphorylation of CtIP by CDK activates DNA resection in the S phase, while the phosphorylation of CtIP by PLK1 disrupts its stimulation of DNA2, attenuating long-range resection later in the cell cycle.
GENES & DEVELOPMENT
(2023)
Review
Microbiology
Benoit Arcangioli, Serge Gangloff
Summary: This article describes how Schizosaccharomyces pombe, a variant of the budding yeast, relies on efficient genetic sex determination and alternating haploid/diploid phases to achieve high reproductive efficiency in response to environmental conditions. By exploring the mating-type switching process and the interaction between genetics and epigenetics, it underscores the significance of basic research in gaining a better understanding of chromatin biology.
MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS
(2023)
Article
Biochemistry & Molecular Biology
Abdul B. Hayran, Nina B. Liabakk, Per A. Aas, Anna Kusnierczyk, Cathrine B. Vagbo, Antonio Sarno, Tobias S. Iveland, Konika Chawla, Astrid Zahn, Javier M. Di Noia, Geir Slupphaug, Bodil Kavli
Summary: Activation-induced cytidine deaminase (AID) interacts with replication protein A (RPA) to promote conversion of cytosine to uracil in immunoglobulin (Ig) genes. Uracil-DNA glycosylase (UNG) plays a crucial role in Ig diversification and genome repair through its interaction with AID. The study shows that the UNG:RPA interaction is important for class switch recombination (CSR) and repair of AID-induced uracil, but has no significant impact on total genomic uracil levels.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Xuefei Zhang, Hye Suk Yoon, Aimee M. Chapdelaine-Williams, Nia Kyritsis, Frederick W. Alt
Summary: This study reveals the critical role of 3' IgH CBEs in regulating gene transcription and joining during CSR processes, especially in focusing transcriptional activities on upstream C-H locus targets.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Cell Biology
Tara Hicks, Shalini Trivedi, Mikayla Eppert, Richard Bowman, Hui Tian, Amna Dafalla, Caroline Crahan, Sarit Smolikove, Nicola Silva
Summary: Faithful chromosome segregation into gametes relies on Spo11-induced DNA double-strand breaks (DSBs). In this study, the authors investigate the temporal dynamics of Spo11 activity in Caenorhabditis elegans and find that DSB induction occurs from early meiotic prophase I to mid-late pachynema. Late DSBs are essential for crossover formation and are preferentially processed by EXO-1 and DNA-2.
Article
Immunology
Parisa Amirifar, Mahya Mehrmohamadi, Mohammad Reza Ranjouri, Seyed Mohammad Akrami, Nima Rezaei, Ali Saberi, Reza Yazdani, Hassan Abolhassani, Asghar Aghamohammadi
Summary: The study identified variants associated with the antigen processing and presentation pathway, as well as variants in four genes involved in DNA double-strand breaks repair signaling in a group of A-T patients. These additional genetic influences may explain the heterogeneity in the CSR defect phenotype among A-T patients.
JOURNAL OF CLINICAL IMMUNOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Cathrine Scheepers, Simone I. Richardson, Thandeka Moyo-Gwete, Penny L. Moore
Summary: In this review, the significance of different antibody isotypes for HIV-1 neutralization breadth and potency is discussed, along with how this knowledge can be utilized to enhance passive and active immunization against HIV-1.
TRENDS IN MOLECULAR MEDICINE
(2022)
Article
Multidisciplinary Sciences
Jinhua Han, Li Wan, Guixing Jiang, Liping Cao, Feiyu Xia, Tian Tian, Xiaomei Zhu, Mingjie Wu, Michael S. Y. Huen, Yi Wang, Ting Liu, Jun Huang
Summary: This study identifies a novel regulatory mechanism that modulates the activity of CtIP at DSBs and the extent of end resection through ATM-dependent sequential posttranslational modification of CtIP.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Koen K. A. Van Rompay, Lark L. Coffey, Tania Kapoor, Anna Gazumyan, Rebekah I. Keesler, Andrea Jurado, Avery Peace, Marianna Agudelo, Jennifer Watanabe, Jodie Usachenko, Anil Singapuri, Ramya Immareddy, Amir Ardeshir, Jackson B. Stuart, Stylianos Bournazos, Jeffrey V. Ravetch, Paul J. Balderes, Ivo C. Lorenz, Shannon R. Esswein, Jennifer R. Keeffe, Pamela J. Bjorkman, Qiao Wang, Charles M. Rice, Margaret R. MacDonald, Michel C. Nussenzweig, Davide F. Robbiani
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Multidisciplinary Sciences
Shannon R. Esswein, Harry B. Gristick, Andrea Jurado, Avery Peace, Jennifer R. Keeffe, Yu E. Lee, Alisa V. Voll, Mohsan Saeed, Michel C. Nussenzweig, Charles M. Rice, Davide F. Robbiani, Margaret R. MacDonald, Pamela J. Bjorkman
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Immunology
Alexandra Schafer, Frauke Muecksch, Julio C. C. Lorenzi, Sarah R. Leist, Melissa Cipolla, Stylianos Bournazos, Fabian Schmidt, Rachel M. Maison, Anna Gazumyan, David R. Martinez, Ralph S. Baric, Davide F. Robbiani, Theodora Hatziioannou, Jeffrey Ravetch, Paul D. Bieniasz, Richard A. Bowen, Michel C. Nussenzweig, Timothy P. Sheahan
Summary: The study shows that combined use of hu-mAbs is effective for prevention and therapy of SARS-CoV-2 infection, but in vivo protection is influenced by intact effector function.
JOURNAL OF EXPERIMENTAL MEDICINE
(2021)
Article
Multidisciplinary Sciences
Christian Gaebler, Zijun Wang, Julio C. C. Lorenzi, Frauke Muecksch, Shlomo Finkin, Minami Tokuyama, Alice Cho, Mila Jankovic, Dennis Schaefer-Babajew, Thiago Y. Oliveira, Melissa Cipolla, Charlotte Viant, Christopher O. Barnes, Yaron Bram, Gaelle Breton, Thomas Hagglof, Pilar Mendoza, Arlene Hurley, Martina Turroja, Kristie Gordon, Katrina G. Millard, Victor Ramos, Fabian Schmidt, Yiska Weisblum, Divya Jha, Michael Tankelevich, Gustavo Martinez-Delgado, Jim Yee, Roshni Patel, Juan Dizon, Cecille Unson-O'Brien, Irina Shimeliovich, Davide F. Robbiani, Zhen Zhao, Anna Gazumyan, Robert E. Schwartz, Theodora Hatziioannou, Pamela J. Bjorkman, Saurabh Mehandru, Paul D. Bieniasz, Marina Caskey, Michel C. Nussenzweig
Summary: After infection with SARS-CoV-2, antibody levels against the spike protein decrease significantly, but the number of memory B cells remain unchanged, indicating an evolving humoral response at 6.2 months after infection.
Article
Cell Biology
Zijun Wang, Julio C. C. Lorenzi, Frauke Muecksch, Shlomo Finkin, Charlotte Viant, Christian Gaebler, Melissa Cipolla, Hans-Heinrich Hoffman, Thiago Y. Oliveira, Deena A. Oren, Victor Ramos, Lilian Nogueira, Eleftherios Michailidis, Davide F. Robbiani, Anna Gazumyan, Charles M. Rice, Theodora Hatziioannou, Paul D. Bieniasz, Marina Caskey, Michel C. Nussenzweig
Summary: The IgA response to SARS-CoV-2 was characterized in a cohort of 149 convalescent individuals after COVID-19 diagnosis. IgA responses in plasma generally correlated with IgG responses, and B cells producing IgM, IgG, and IgA were derived from common progenitor cells. Notably, IgA dimers were found to be 15 times more potent than IgA monomers against SARS-CoV-2, suggesting their potential value for protection and vaccine efficacy.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Hematology
Tomasz Sewastianik, Juerg R. Straubhaar, Jian-Jun Zhao, Mehmet K. Samur, Keith Adler, Helen E. Tanton, Vignesh Shanmugam, Omar Nadeem, Peter S. Dennis, Vinodh Pillai, Jianli Wang, Meng Jiang, Jianhong Lin, Ying Huang, Daniel Brooks, Mary Bouxsein, David M. Dorfman, Geraldine S. Pinkus, Davide F. Robbiani, Irene M. Ghobrial, Bogdan Budnik, Petr Jarolim, Nikhil C. Munshi, Kenneth C. Anderson, Ruben D. Carrasco
Summary: The deletion of miR-15a/16-1 cluster in murine GC B cells induces moderate but widespread molecular and functional changes, leading to the development of mature B-cell neoplasms resembling human extramedullary plasmacytoma and lymphoma. The low expression levels of miR-15a/16 in human primary EP, primarily associated with del(13q) loss, highlights the tumor-suppressor role of this cluster in plasma cell and B-cell malignancies.
Article
Immunology
Marianna Agudelo, Martin Palus, Jennifer R. Keeffe, Filippo Bianchini, Pavel Svoboda, Jiri Salat, Avery Peace, Anna Gazumyan, Melissa Cipolla, Tania Kapoor, Francesca Guidetti, Kai-Hui Yao, Jana Elsterova, Dana Teislerova, Ales Chrdle, Vaclav Honig, Thiago Oliveira, Anthony P. West, Yu E. Lee, Charles M. Rice, Margaret R. MacDonald, Pamela J. Bjorkman, Daniel Ruzek, Davide F. Robbiani, Michel C. Nussenzweig
Summary: The study revealed the human neutralizing antibody response to TBEV, showing that the most potent neutralizing antibodies were found in individuals who recovered from natural infection. These antibodies also neutralized other tick-borne flaviviruses, and structural analysis identified a conserved epitope near the lateral ridge of EDIII. Prophylactic or early therapeutic antibody administration was effective at low doses in mice lethally infected with TBEV.
JOURNAL OF EXPERIMENTAL MEDICINE
(2021)
Article
Multidisciplinary Sciences
Raoul De Gasparo, Mattia Pedotti, Luca Simonelli, Petr Nickl, Frauke Muecksch, Irene Cassaniti, Elena Percivalle, Julio C. C. Lorenzi, Federica Mazzola, Davide Magri, Tereza Michalcikova, Jan Haviernik, Vaclav Honig, Blanka Mrazkova, Natalie Polakova, Andrea Fortova, Jolana Tureckova, Veronika Iatsiuk, Salvatore Di Girolamo, Martin Palus, Dagmar Zudova, Petr Bednar, Ivana Bukova, Filippo Bianchini, Dora Mehn, Radim Nencka, Petra Strakova, Oto Pavlis, Jan Rozman, Sabrina Gioria, Jose Camilla Sammartino, Federica Giardina, Stefano Gaiarsa, Qiang Pan-Hammarstrom, Christopher O. Barnes, Pamela J. Bjorkman, Luigi Calzolai, Antonio Piralla, Fausto Baldanti, Michel C. Nussenzweig, Paul D. Bieniasz, Theodora Hatziioannou, Jan Prochazka, Radislav Sedlacek, Davide F. Robbiani, Daniel Ruzek, Luca Varani
Summary: The bispecific IgG1-like molecule CoV-X2 can simultaneously bind two independent sites on the RBD, prevent spike binding to ACE2, neutralize SARS-CoV-2 and its variants, and protect mice from disease in a mouse model of SARS-CoV-2 infection. This demonstrates the feasibility and efficacy of targeting non-overlapping RBD epitopes with IgG-like bispecific antibodies.
Editorial Material
Immunology
Davide F. Robbiani, Daniel Ruzek
Summary: The NS1 protein of flaviviruses has become a focus of research for its potential in vaccine and immunotherapeutic development. However, a recent study has revealed a potential dark side to NS1, linking it to the development of self-reactive antibodies.
JOURNAL OF EXPERIMENTAL MEDICINE
(2021)
Article
Multidisciplinary Sciences
Allison J. Greaney, Tyler N. Starr, Christopher O. Barnes, Yiska Weisblum, Fabian Schmidt, Marina Caskey, Christian Gaebler, Alice Cho, Marianna Agudelo, Shlomo Finkin, Zijun Wang, Daniel Poston, Frauke Muecksch, Theodora Hatziioannou, Paul D. Bieniasz, Davide F. Robbiani, Michel C. Nussenzweig, Pamela J. Bjorkman, Jesse D. Bloom
Summary: The study found that although the human immune system can produce antibodies that target diverse RBD epitopes, in practice, the polyclonal response to infection tends to be skewed towards a single class of antibodies targeting an epitope that is already undergoing rapid evolution.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Charly R. Good, M. Angela Aznar, Shunichiro Kuramitsu, Parisa Samareh, Sangya Agarwal, Greg Donahue, Kenichi Ishiyama, Nils Wellhausen, Austin K. Rennels, Yujie Ma, Lifeng Tian, Sonia Guedan, Katherine A. Alexander, Zhen Zhang, Philipp C. Rommel, Nathan Singh, Karl M. Glastad, Max W. Richardson, Keisuke Watanabe, Janos L. Tanyi, Mark H. O'Hara, Marco Ruella, Simon F. Lacey, Edmund K. Moon, Stephen J. Schuster, Steven M. Albelda, Lewis L. Lanier, Regina M. Young, Shelley L. Berger, Carl H. June
Summary: CAR T cell therapy has achieved success in hematological malignancies but faces challenges in solid tumors due to CAR T cell exhaustion. Dysfunction of CAR T cells in solid tumors is associated with CD8+ T-to-NK-like T cell transition, and genetic downregulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy.
Review
Immunology
Nils Wellhausen, Sangya Agarwal, Philipp C. Rommel, Saar Gill, Carl H. June
Summary: T cells engineered with transgenes such as CAR or modified TCR have become a new pillar of cancer therapy. The use of CRISPR/Cas gene-editing tools provides even stronger and more precise control over the fate and function of engineered T cell therapies. This review summarizes the CRISPR/Cas techniques used in preclinical research and outlines those being tested in clinical trials.
CURRENT OPINION IN IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Anusha Kalbasi, Mikko Siurala, Leon L. Su, Mito Tariveranmoshabad, Lora K. Picton, Pranali Ravikumar, Peng Li, Jian-Xin Lin, Helena Escuin-Ordinas, Tong Da, Sarah V. Kremer, Amy L. Sun, Sofia Castelli, Sangya Agarwal, John Scholler, Decheng Song, Philipp C. Rommel, Enrico Radaelli, Regina M. Young, Warren J. Leonard, Antoni Ribas, Carl H. June, K. Christopher Garcia
Summary: Synthetic receptor signaling has the potential to enhance the functions of adoptively transferred T cells, improving their ability to treat solid tumors. By designing chimeric receptors with an orthogonal IL-2 receptor extracellular domain fused with the intracellular domain of receptors for common gamma-chain cytokines IL-4, IL-7, IL-9, and IL-21, T cells can be activated to elicit corresponding gamma(e) cytokine signals. This activation leads to improved anti-tumor efficacy in challenging mouse models of melanoma and pancreatic cancer.
Article
Immunology
Filippo Bianchini, Virginia Crivelli, Morgan E. Abernathy, Concetta Guerra, Martin Palus, Jonathan Muri, Harold Marcotte, Antonio Piralla, Mattia Pedotti, Raoul De Gasparo, Luca Simonelli, Milos Matkovic, Chiara Toscano, Maira Biggiogero, Veronica Calvaruso, Pavel Svoboda, Tomas Cervantes Rincon, Tommaso Fava, Lucie Podesvova, Akanksha A. Shanbhag, Andrea Celoria, Jacopo Sgrignani, Michal Stefanik, Vaclav Honig, Veronika Pranclova, Tereza Michalcikova, Jan Prochazka, Giuditta Guerrini, Dora Mehn, Annalisa Clabbattini, Hassan Abolhassani, David Jarrossay, Mariagrazia Uguccioni, Donata Medaglini, Qiang Pan-Hammarstroem, Luigi Calzolai, Daniel Fernandez, Fausto Baldanti, Alessandra Franzetti-Pellanda, Christian Garzoni, Radislav Sedlacek, Daniel Ruzek, Luca Varani, Andrea Cavalli, Christopher O. Barnes, Davide F. Robbiani
Summary: Using coldspot-guided antibody discovery, neutralizing antibodies to highly conserved viral epitopes were identified. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1 and synergizes with antibody rbd.042 for neutralization.
SCIENCE IMMUNOLOGY
(2023)
Article
Immunology
Jonathan Muri, Valentina Cecchinato, Andrea Cavalli, Akanksha A. A. Shanbhag, Milos Matkovic, Maira Biggiogero, Pier Andrea Maida, Jacques Moritz, Chiara Toscano, Elaheh Ghovehoud, Raffaello Furlan, Franca Barbic, Antonio Voza, Guendalina De Nadai, Carlo Cervia, Yves Zurbuchen, Patrick Taeschler, Lilly A. Murray, Gabriela Danelon-Sargenti, Simone Moro, Tao Gong, Pietro Piffaretti, Filippo Bianchini, Virginia Crivelli, Lucie Podesvova, Mattia Pedotti, David Jarrossay, Jacopo Sgrignani, Sylvia Thelen, Mario Uhr, Enos Bernasconi, Andri Rauch, Antonio Manzo, Adrian Ciurea, Marco B. L. Rocchi, Luca Varani, Bernhard Moser, Barbara Bottazzi, Marcus Thelen, Brian A. Fallon, Onur Boyman, Alberto Mantovani, Christian Garzoni, Alessandra Franzetti-Pellanda, Mariagrazia Uguccioni, Davide F. Robbiani
Summary: We found that antibodies against specific chemokines are commonly present in COVID-19 convalescents and are associated with favorable disease outcomes and a decreased risk of long COVID development at 1 year post-infection. These chemokine antibodies are also found in HIV-1 infection and autoimmune disorders, but target different chemokines compared to COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bind to the chemokine N-loop impair cell migration. Naturally occurring chemokine antibodies may modulate the inflammatory response and have therapeutic potential.