Article
Biochemistry & Molecular Biology
Ann-Kathrin Mehnert, Marco Prorocic, Annick Dujeancourt-Henry, Sebastian Hutchinson, Richard McCulloch, Lucy Glover
Summary: In Trypanosoma brucei, RAD50 and MRE11 are essential for RAD51-dependent homologous recombination and phosphorylation of histone H2A following a DNA double strand break. RAD50 suppresses DSB repair using short stretches of homology at a subtelomeric locus, while MRE11 directs DSB resection at the same locus. Loss of either MRE11 or RAD50 leads to increased diversity of expressed VSG variants following DSB repair, suggesting that MRN promotes stringent homologous recombination at subtelomeric loci and restrains antigenic variation.
NUCLEIC ACIDS RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Matvey Mikhailovich Murashko, Ekaterina Mikhailovna Stasevich, Anton Markovich Schwartz, Dmitriy Vladimirovich Kuprash, Aksinya Nicolaevna Uvarova, Denis Eriksonovich Demin
Summary: Incorrect repair of DNA double-strand breaks leading to chromosomal rearrangements is a major cause of oncogenesis. Recent studies have highlighted the key role of various types of RNA in the formation, recognition, and repair of DSBs, with gene mutations or changes in RNA expression levels potentially leading to DNA repair defects and increased chromosome aberration frequency. Additionally, certain RNAs have been shown to stimulate long-range chromosomal rearrangements, and further research is needed to understand how RNA mediates specific chromosomal rearrangements.
Article
Genetics & Heredity
Mariame D. Diabate, Muhtadi J. Islam, Gregory Nagy, Tapahsama J. Banerjee, Shruti Dhar, Nahum J. Smith, Aleksandra Adamovich, Lea J. Starita, Jeffrey Parvin
Summary: Functional analysis of 2172 variants in the BRCA1 gene showed that pathogenic variants have a loss of function in DNA repair, while benign variants are functionally normal in a multiplexed assay. These functional determinations can provide evidence for clinical geneticists to evaluate variants of uncertain significance in BRCA1.
Editorial Material
Biotechnology & Applied Microbiology
Megumi Ishii, Tetsuya Ishii
Summary: This passage discusses whether genome-edited agricultural products should be considered genetically modified organisms (GMOs) and how to prove definitively that a genome-edited organism does not contain exogenous DNA, taking social aspects into account.
TRENDS IN BIOTECHNOLOGY
(2022)
Article
Multidisciplinary Sciences
Jakub Wiktor, Arvid H. Gynna, Prune Leroy, Jimmy Larsson, Giovanna Coceano, Ilaria Testa, Johan Elf
Summary: Homologous recombination is crucial for accurate DNA repair, with repair of double-stranded DNA breaks in E. coli completed in approximately 15 minutes. The search for homologous repair templates takes less than 9 minutes and is mediated by a thin and highly dynamic RecA filament stretching throughout the cell. This model effectively reduces search dimensionality, with search time consistent across different cell lengths and DNA amounts.
Article
Multidisciplinary Sciences
Afroze Chimthanawala, Jyotsana J. Parmar, Sujan Kumar, Krishnan S. Iyer, Madan Rao, Anjana Badrinarayanan
Summary: This study uncovers three key elements of homology search driven by RecN: the mobility of a finite segment of RecA, dynamic changes in filament length, and the ability to conduct multiple pole-to-pole traversals.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Cell Biology
Juliette Dabin, Margherita Mori, Sophie E. Polo
Summary: This review summarizes recent advances in understanding the coordination between chromatin maintenance and the DNA damage response (DDR) in the cell nucleus. The authors discuss how the DDR affects chromatin marks, organization, and mobility, and how chromatin alterations contribute to the DDR. They also present current knowledge of the molecular mechanisms underlying these processes in physiological and pathological conditions, and highlight unanswered questions in this field.
CURRENT OPINION IN CELL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Yuning Jiang, Jason C. Yam, Wai Kit Chu
Summary: Retinoblastoma, the most common intraocular cancer in childhood, is typically treated with chemotherapeutic agents. Research shows that the PARP inhibitor olaparib can effectively kill retinoblastoma cells after inducing DNA double-strand breaks, especially when used in combination with etoposide to enhance cell death. This combination treatment may allow for lower dosages of etoposide to be used, potentially leading to a more stable genome with reduced levels of DNA double-strand breaks.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Microbiology
Jun Huang, David E. Cook
Summary: This review summarizes and compares the molecular mechanism, hierarchy, and regulation of four DNA double-strand break repair pathways in animal and fungal models, and connects them to genome engineering outcomes and biased genome evolution in filamentous pathogens.
FEMS MICROBIOLOGY REVIEWS
(2022)
Review
Genetics & Heredity
Alice Libri, Timea Marton, Ludovic Deriano
Summary: DNA double-strand breaks are highly toxic and can be repaired via multiple DNA repair pathways. During V(D)J recombination, certain parameters restrict the repair of DSBs to the non-homologous end-joining pathway.
FRONTIERS IN GENETICS
(2022)
Article
Genetics & Heredity
Xiaoli Ping, Jeremy M. Stark
Summary: This study reveals that disruption of O-GlcNAcylation reduces repair pathways involving homology, while not affecting chromosomal break end joining and increasing homology-directed gene targeting. It also decreases clonogenic survival, modifies cell cycle profiles, particularly increasing G1-phase cells. Furthermore, the influence of O-GlcNAcylation on HDR and homology-directed gene targeting is dependent on RAD52.
Article
Biology
Nadia Vertti-Quintero, Ethan Levien, Lucie Poggi, Ariel Amir, Guy-Franck Richard, Charles N. N. Baroud
Summary: This study demonstrates the use of microfluidic device to study DSBR at a single-cell level in yeast. The dynamics of DSBR were analyzed and a differential equation model was developed to obtain repair process rates. The study identified three types of DSB repair events that were previously unrecognized.
Article
Biochemistry & Molecular Biology
Laura Cheradame, Ida Chiara Guerrera, Julie Gaston, Alain Schmitt, Vincent Jung, Nicolas Goudin, Marion Pouillard, Nina Radosevic-Robin, Mauro Modesti, Jean-Gabriel Judde, Stefano Cairo, Vincent Goffin
Summary: STING downregulation decreases cell survival and increases sensitivity to genotoxic treatment in breast cancer cell lines, affecting DNA Damage Response. The localization of STING at the inner nuclear membrane in breast cancer cells is independent of its partner cGAS and canonical pathway. High STING expression is associated with increased risk of relapse in breast and ovarian cancer patients receiving adjuvant chemotherapy.
Article
Biochemistry & Molecular Biology
Ioannis Emmanouilidis, Natalia Fili, Alexander W. Cook, Yukti Hari-Gupta, Alia dos Santos, Lin Wang, Marisa L. Martin-Fernandez, Peter J. I. Ellis, Christopher P. Toseland
Summary: Mammalian cells are constantly exposed to various DNA damaging events, leading to the activation of DNA repair pathways. Cas9-based genomic intervention allows for induced DSBs at defined quantities and locations across the human genome, utilizing custom-designed promiscuous guide RNAs based on in silico predictions. This provides a generic, low-cost, and rapid methodology for inducing controlled DNA damage in cell culture models.
Article
Chemistry, Multidisciplinary
Deepak J. Prabhu, Ujjayinee Ray, Anjaly Rajeev, Reshma Joy, Abi Thoppilan George, Jinu George, Sathees C. Raghavan, Franklin John
Summary: A new multicomponent reaction involving sulfonamide-conjugated ketenimines is reported. The reaction is atom economical and stereoselective, generating key intermediates for further synthesis of compounds. The synthesized molecules exhibit potential for targeting the NHEJ pathway and have cytotoxic abilities. Computational studies and in vitro biological assays support the findings.
Article
Biochemistry & Molecular Biology
Anna Trenaman, Lucy Glover, Sebastian Hutchinson, David Horn
NUCLEIC ACIDS RESEARCH
(2019)
Article
Multidisciplinary Sciences
Susan Wyllie, Stephen Brand, Michael Thomas, Manu De Rycker, Chun-wa Chung, Imanol Pena, Ryan P. Bingham, Juan A. Bueren-Calabuig, Juan Cantizani, David Cebrian, Peter D. Craggs, Liam Ferguson, Panchali Goswami, Judith Hobrath, Jonathan Howe, Laura Jeacock, Eun-Jung Ko, Justyna Korczynska, Lorna MacLean, Sujatha Manthri, Maria S. Martinez, Lydia Mata-Cantero, Sonia Moniz, Andrea Nuhs, Maria Osuna-Cabello, Erika Pinto, Jennifer Riley, Sharon Robinson, Paul Rowland, Frederick R. C. Simeons, Yoko Shishikura, Daniel Spinks, Laste Stojanovski, John Thomas, Stephen Thompson, Elisabet Viayna Gaza, Richard J. Wall, Fabio Zuccotto, David Horn, Michael A. J. Ferguson, Alan H. Fairlamb, Jose M. Fiandor, Julio Martin, David W. Gray, Timothy J. Miles, Ian H. Gilbert, Kevin D. Read, Maria Marco, Paul G. Wyatt
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2019)
Article
Microbiology
Lucy Glover, Catarina A. Marques, Olga Suska, David Horn
Article
Multidisciplinary Sciences
Joana Faria, Lucy Glover, Sebastian Hutchinson, Cordula Boehm, Mark C. Field, David Horn
NATURE COMMUNICATIONS
(2019)
Article
Biochemistry & Molecular Biology
Martin Zoltner, Gustavo D. Campagnaro, Gergana Taleva, Alana Burrell, Michela Cerone, Ka-Fai Leung, Fiona Achcar, David Horn, Sue Vaughan, Catarina Gadelha, Alena Zikova, Michael P. Barrett, Harry P. de Koning, Mark C. Field
JOURNAL OF BIOLOGICAL CHEMISTRY
(2020)
Article
Microbiology
Joana Faria, Vanessa Luzak, Laura S. M. Muller, Benedikt G. Brink, Sebastian Hutchinson, Lucy Glover, David Horn, T. Nicolai Siegel
Summary: The study reveals a mechanism in Trypanosoma brucei where a single expressed antigen-coding gene interacts with a major messenger RNA splicing locus in a specific nuclear compartment, ensuring monogenic expression. Specific proteins VEX1 and VEX2 are associated with an antigen exclusion complex, playing a role in this process of antigen transcription and mRNA splicing. Depletion of VEX2 results in loss of monogenic antigen expression and increased interactions between previously silent antigen genes and the splicing locus.
NATURE MICROBIOLOGY
(2021)
Review
Parasitology
David Horn
Summary: Genome-scale genetic screens have played a crucial role in African trypanosomes by uncovering mechanisms related to drug resistance, metabolism, and gene expression control. They have also been effective in identifying potential antitrypanosomal drug targets.
TRENDS IN PARASITOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Simone Altmann, Eva Rico, Sandra Carvalho, Melanie Ridgway, Anna Trenaman, Hannah Donnelly, Michele Tinti, Susan Wyllie, David Horn
Summary: This study reports a simple method for rapid and precise editing of priority drug targets in trypanosomatids. By targeting and editing drug targets, combined with sequencing technology, potential impacts on drug efficacy can be assessed quickly.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Microbiology
Gustavo Bravo Ruiz, Michele Tinti, Melanie Ridgway, David Horn
Summary: VSG expression plays a crucial role in parasite virulence and is a fascinating subject in extreme biology. This study identified three candidate VSG regulators and demonstrated the role of CFB2 in controlling VSG expression through the VSG 3' UTR. Additionally, insights into the connections between VSG expression control, ribosomal protein expression, and cytokinesis were revealed.
Correction
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
NATURE REVIEWS MICROBIOLOGY
(2022)
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are major causes of death and illness, particularly in low- and middle-income countries. The development of new medicines for leishmaniasis and Chagas disease is urgently needed, with limited progress in the clinical pipeline for Chagas disease. This review provides an overview of recent advances in understanding the biology of these pathogens, with a focus on drug discovery, as well as the development of new drug candidates and potential solutions to overcome challenges in clinical development.
NATURE REVIEWS MICROBIOLOGY
(2023)
Article
Multidisciplinary Sciences
Catarina A. Marques, Melanie Ridgway, Michele Tinti, Andrew Cassidy, David Horn
Summary: In this study, a genome-wide RNA-interference library screen was used to investigate the cell cycle defects in Trypanosoma brucei. The results provide comprehensive functional genomic evidence for the known and novel machineries, pathways, and regulators that coordinate trypanosome cell cycle progression.
NATURE COMMUNICATIONS
(2022)
Article
Microbiology
Douglas Escrivani, Viktor Scheidt, Michele Tinti, Joana Faria, David Horn
Summary: Some pathogens use antigenic variation to evade mammalian host adaptive immune responses. African trypanosomes employ variant surface glycoproteins (VSGs) to continually switch their active VSGs and avoid immune recognition. Switched trypanosomes compete in a predictable manner that is dependent on the activated VSG, and the population of cells that activates minichromosome derived VSGs has a competitive advantage.
Article
Microbiology
Anna Trenaman, Michele Tinti, Abdelmadjid Atrih, David Horn
Summary: Nucleoside analogs are widely used as anti-infective agents, but their potential as anti-parasitic agents has not been fully explored. This study identified two proteins, Tb927.6.2800 and HD82, associated with purine analog resistance in African trypanosomes. The findings also validated two nucleoside kinases involved in pro-drug activation. HD82, related to the mammalian nuclear viral restriction factor SAMHD1, sensitized trypanosomes to nucleoside analogs by reducing native nucleotide pools. This study provides insights into nucleoside/nucleotide metabolism and nucleoside analog resistance in trypanosomatids.
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are causing significant death and morbidity, especially in low- and middle-income countries. There is a critical need for new medications for leishmaniasis and Chagas disease, while the clinical development pipeline for Chagas disease remains sparse. This review discusses recent advancements in understanding the biology of these pathogens, with a focus on drug discovery, and explores progress in developing new drug candidates and identifying potential molecular targets. The challenges in developing new clinical candidates are also discussed, along with potential solutions to overcome these hurdles.
NATURE REVIEWS MICROBIOLOGY
(2023)