Review
Biochemistry & Molecular Biology
Go Watanabe, Michael R. Lieber
Summary: Nonhomologous DNA end joining is the major pathway for repairing double-strand breaks in cells, and Artemis serves as the major nuclease in this process. The activity of Artemis is tightly regulated by the DNA-PKcs kinase, which interacts with Artemis and is activated by broken DNA ends. Studying the structure of the Artemis:DNA-PKcs complex and its relevance to biochemistry and the immune system provides important insights into the cellular DNA repair process.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Plant Sciences
Fabienne Gehrke, Angelina Schindele, Holger Puchta
Summary: Heritable plant chromosome engineering can be achieved in somatic cells using CRISPR/Cas to induce nonhomologous double-strand break repair pathways. This technology allows for large-scale restructuring of plant chromosomes, including duplications, inversions, and translocations. The use of nonhomologous end joining pathways in somatic cells facilitates efficient chromosomal rearrangements. This breakthrough has the potential to revolutionize plant breeding.
Review
Genetics & Heredity
Dipayan Ghosh, Sathees C. Raghavan
Summary: This article discusses key proteins in the NHEJ repair pathway, such as PAXX, MRI/CYREN, TDP-43, IFFO1, ERCC6L2, and RNase H2, and their roles in the repair of double-strand breaks in the cell nucleus.
TRENDS IN GENETICS
(2021)
Article
Multidisciplinary Sciences
Ming Tang, Guofang Chen, Bo Tu, Zhiyi Hu, Yujia Huang, Christopher C. DuFort, Xiaoping Wan, Zhiyong Mao, Yongzhong Liu, Wei-Guo Zhu, Wen Lu
Summary: DDR has different effects on cancer susceptibility and drug resistance. Recent studies showed that DDR inhibitors impact immune surveillance, however, the underlying mechanism is poorly understood. This study reveals that methyltransferase SMYD2 plays a crucial role in nonhomologous end joining repair (NHEJ), promoting tumor cell adaptability to radiotherapy. SMYD2 is mobilized to chromatin upon DNA damage and methylates Ku70, leading to increased recruitment of Ku70/Ku80/DNA-PKcs complex. Inhibition of SMYD2 or knockdown of SMYD2 results in persistent DNA damage and improper repair, leading to cytosolic DNA accumulation and activation of cGAS-STING pathway, triggering antitumor immunity by infiltration and activation of cytotoxic CD8+ T cells. This study reveals a novel role of SMYD2 in regulating NHEJ pathway and innate immune responses, suggesting SMYD2 as a promising therapeutic target for cancer treatment.
Article
Biochemistry & Molecular Biology
Huiming Lu, Qin Zhang, Daniel J. Laverty, Andrew C. Puncheon, Mathew M. Augustine, Gareth J. Williams, Zachary D. Nagel, Benjamin P. C. Chen, Anthony J. Davis
Summary: In this study, it was found that ATM drives the DNA damage response by modulating multiple signal transduction and DNA repair pathways. ATM phosphorylates DNA-PKcs at threonine 4102 (T4102) in response to DSBs, promoting NHEJ-dependent repair and increasing genomic stability. These findings highlight the key role of ATM in DNA repair.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemical Research Methods
Xiaoqin Liu, Mengmeng Liu, Jin Zhang, Yizhao Chang, Zhiyong Cui, Boyang Ji, Jens Nielsen, Qingsheng Qi, Jin Hou
Summary: The study revealed the distribution of NHEJ-mediated integration on chromosomes for the first time and demonstrated its potential for constructing a genome-scale trackable mutagenesis library. The research showed that the integration inserts DNA randomly across chromosomes and exhibits a preference for transcriptional regulatory regions. This approach proved to be effective in rapidly identifying new targets for improving beta-carotene biosynthesis and acetic acid tolerance.
ACS SYNTHETIC BIOLOGY
(2022)
Article
Microbiology
Wen-Wei Zhang, Douglas G. Wright, Lynn Harrison, Greg Matlashewski
Summary: In this study, it was found that the protozoan parasite Leishmania lacks a functional NHEJ pathway but retains Ku70 and Ku80 proteins. Ku is involved in DSB repair and affects the repair outcome through different mechanisms. Additionally, Ku is required for the healthy growth of the parasite but is not important for maintaining telomere lengths.
Article
Chemistry, Multidisciplinary
Daniel Abegg, Martin Tomanik, Nan Qiu, Dany Pechalrieu, Anton Shuster, Bruno Commare, Antonio Togni, Seth B. Herzon, Alexander Adibekian
Summary: The tetrafluoroalkyl benziodoxole (TFBX) has emerged as a powerful cysteine-selective chemoproteomic probe, featuring superior target occupancy, faster labeling kinetics, and broader proteomic coverage compared to traditional cysteine-reactive probes. This new probe has been demonstrated to successfully identify cellular targets of (-)-myrocin G, leading to the discovery of the first reported inhibitors of the biomedically important protein XRCC5. Additionally, this probe disrupts the interaction of XRCC5 with DNA, sensitizing cancer cells to chemotherapeutic agents and UV-light-induced DNA damage.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Genetics & Heredity
Danyu Song, Xiaomei Li, Wei Wei, Xueqin Liu, Lin Wu, Hui Xiong
Summary: In this study, two siblings with Emery-Dreifuss muscular dystrophy (EDMD) were reported in a family, with one showing symptoms of heart dilation and muscle weakness, while the other had elevated levels of creatine kinase. Genetic analysis revealed complete deletion of the EMD gene and a rearrangement in the FLNA gene in both patients, supporting the pathogenic mechanism of microhomology-mediated nonhomologous end joining.
FRONTIERS IN GENETICS
(2021)
Article
Biochemistry & Molecular Biology
Raquel Gago-Fuentes, Valentyn Oksenych
Summary: NHEJ factors XLF, DNA-PKcs, and PAXX play crucial roles in maintaining neural stem and progenitor cell populations and neurodevelopment in mammals, particularly evident in double knockout models.
Article
Genetics & Heredity
Christina A. Gerodimos, Go Watanabe, Michael R. Lieber
Summary: The nucleosomal state imposes strict constraints on NHEJ nuclease and ligase activities, and the presence of nucleosome-wrapped DNA ends can affect the joining process.
Article
Biochemistry & Molecular Biology
Maria Ovejero-Sanchez, Jorge Rubio-Heras, Maria del Carmen Vicente de la Pena, Laura San-Segundo, Jesus Perez-Losada, Rogelio Gonzalez-Sarmiento, Ana Belen Herrero
Summary: Ovarian cancer is a deadly malignancy that requires more effective treatments. The combination of chloroquine with nonhomologous end joining inhibitors has been found to inhibit proliferation and induce apoptosis in ovarian cancer cell lines. Additionally, the combination with a pan-histone deacetylase inhibitor enhances the efficacy of chloroquine. These drug combinations could represent new therapeutic strategies against ovarian cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Benjamin M. Stinson, Joseph J. Loparo
Summary: DNA double-strand breaks are mainly repaired through nonhomologous end joining (NHEJ) in vertebrates, which requires efficient end synapsis and processing mechanisms to maintain genome stability.
ANNUAL REVIEW OF BIOCHEMISTRY, VOL 90, 2021
(2021)
Article
Cell & Tissue Engineering
Sebastiano Giallongo, Daniela Rehakova, Tommaso Biagini, Oriana Lo Re, Priyanka Raina, Gabriela Lochmanova, Zbynek Zdrahal, Igor Resnick, Pille Pata, Illar Pata, Martin Mistrik, Joao Pedro de Magalhaes, Tommaso Mazza, Irena Koutna, Manlio Vinciguerra
Summary: The study identifies the splicing isoform macroH2A1.1 as a potential regulator of DNA damage repair (DDR) during iPSC reprogramming. MacroH2A1.1 overexpression enhances DDR efficiency through specific activation of the nonhomologous end joining (NHEJ) repair pathway. It also improves iPSC reprogramming, indicating its importance in maintaining genome stability and therapeutic potential.
Article
Andrology
Hui-Yu Dong, Pan Zang, Mei-Ling Bao, Tian-Ren Zhou, Chen-Bo Ni, Lei Ding, Xu-Song Zhao, Jie Li, Chao Liang
Summary: Recent studies have found that the combination of anti-androgen enzalutamide and PARP inhibitor olaparib can significantly inhibit the proliferation and induce apoptosis in AR-positive prostate cancer cells. Bioinformatics analysis revealed that the combination treatment affects nonhomologous end joining and apoptosis pathways. Moreover, enzalutamide enhances the response of prostate cancer cells to the combination therapy by regulating anti-apoptotic and pro-apoptotic genes.
ASIAN JOURNAL OF ANDROLOGY
(2023)
Article
Oncology
Sanjiban Chakrabarty, William F. Quiros-Solano, Maayke M. P. Kuijten, Ben Haspels, Sandeep Mallya, Calvin Shun Yu Lo, Amr Othman, Cinzia Silvestri, Anja van de Stolpe, Nikolas Gaio, Hanny Odijk, Marieke van de Ven, Corrina M. A. de Ridder, Wytske M. van Weerden, Jos Jonkers, Ronald Dekker, Nitika Taneja, Roland Kanaar, Dik C. van Gent
Summary: This study developed a microfluidic platform for evaluating cancer treatment response and predicting drug efficacy in breast and prostate tumors. By culturing tumor slices under controlled growth conditions, the platform allows reliable assessment of chemotherapeutic sensitivity and enables detailed mechanistic studies.
Article
Immunology
Annieck M. Diks, Pauline Versteegen, Cristina Teodosio, Rick J. Groenland, Bas de Mooij, Anne-Marie Buisman, Alba Torres-Valle, Martin Perez-Andres, Alberto Orfao, Guy A. M. Berbers, Jacques J. M. van Dongen, Magdalena A. Berkowska
Summary: This study used high-dimensional flow cytometry to investigate changes in B cells after administration of an acellular pertussis booster vaccine. The results showed that the expansion and maturation of plasma cells were the most significant cellular changes post-vaccination, and were more pronounced in individuals primed with whole-cell vaccine.
Article
Biochemistry & Molecular Biology
Titia G. Meijer, Luan Nguyen, Arne Van Hoeck, Anieta M. Sieuwerts, Nicole S. Verkaik, Marjolijn M. Ladan, Kirsten Ruigrok-Ritstier, Carolien H. M. van Deurzen, Harmen J. G. van de Werken, Esther H. Lips, Sabine C. Linn, Yasin Memari, Helen Davies, Serena Nik-Zainal, Roland Kanaar, John W. M. Martens, Edwin Cuppen, Agnes Jager, Dik C. van Gent
Summary: Germline BRCA1/2 mutation status predicts response to PARP inhibitors in breast cancer patients. Non-germline BRCA1/2 mutations and HRD tumors may also be sensitive to PARP inhibitors. The RECAP test can identify HRD tumors and correlates partially with DNA-based HRD tests. The test also identifies deficiencies in other DNA repair genes.
Article
Multidisciplinary Sciences
Yu-Hsiu Wang, Teresa L. F. Ho, Anushya Hariharan, Hui Chin Goh, Yao Liang Wong, Nicole S. Verkaik, May Yin Lee, Wai Leong Tam, Dik C. van Gent, Ashok R. Venkitaraman, Michael P. Sheetz, David P. Lane
Summary: This study reveals that p53 rapidly accumulates at DNA damage sites and plays a critical role in directing DNA repair dynamics and integrity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Medicine, General & Internal
Gerda M. Verduijn, Marta E. Capala, Nienke D. Sijtsema, Iris Lauwers, Hernandez Juan A. Tamames, Wilma D. Heemsbergen, Aniel Sewnaik, Jose A. Hardillo, Hetty Mast, Yvette van Norden, Maurice P. H. M. Jansen, Aad van der Lugt, Dik C. van Gent, Mischa S. Hoogeman, Bianca Mostert, Steven F. Petit
Summary: This study aims to gain insights into novel potential prognostic biomarkers to predict response to treatment in HPV-negative patients with OPSCC.
Article
Oncology
Nienke Brouwer, Sergio Matarraz, Stefan Nierkens, Mattias Hofmans, Michaela Novakova, Elaine Sobral da Costa, Paula Fernandez, Anne E. Bras, Fabiana Vieira de Mello, Ester Mejstrikova, Jan Philippe, Georgiana Emilia Grigore, Carlos E. Pedreira, Jacques J. M. van Dongen, Alberto Orfao, Vincent H. J. van der Velden
Summary: Acute megakaryoblastic leukemia (AMKL) is a rare and heterogeneous subtype of acute myeloid leukemia (AML). Flowcytometric immunophenotyping can accurately diagnose AMKL and multiple subgroups exist within these patients.
Article
Oncology
Marjolijn M. Ladan, Titia G. Meijer, Nicole S. Verkaik, Zofia M. Komar, Carolien H. M. van Deurzen, Michael A. den Bakker, Roland Kanaar, Dik C. van Gent, Agnes Jager
Summary: This study explores the feasibility of a functional sensitivity test for the chemotherapeutic agents cisplatin and docetaxel on breast cancer tissue slices in culture. The results show that these two agents need to be analyzed differently and the test has been adapted for biopsies from metastatic breast tumors. The test is now ready for evaluation of its predictive value in clinical trials.
Article
Oncology
Anne E. Bras, Sergio Matarraz, Stefan Nierkens, Paula Fernandez, Jan Philippe, Carmen-Mariana Aanei, Fabiana Vieira de Mello, Leire Burgos, Alita J. Van der Sluijs-Gelling, Georgiana Emilia Grigore, Jacques J. M. van Dongen, Alberto Orfao, Vincent H. J. van der Velden
Summary: Flow cytometry plays an important role in the diagnosis of acute myeloid leukemia. This study reports on the construction of a large database of acute myeloid leukemia patients and discusses the quality assessment procedure used. The study shows that obtaining reproducible flow cytometric data across centers is feasible with strict quality assessment.
Article
Oncology
Elen Oliveira, Elaine S. Costa, Juana Ciudad, Giuseppe Gaipa, Lukasz Sedek, Susana Barrena, Tomasz Szczepanski, Chiara Buracchi, Daniela Silvestri, Patricia F. R. Siqueira, Fabiana Mello, Rafael C. Torres, Leonardo M. R. Oliveira, Isabelle V. C. Fay-Neves, Edwin Sonneveld, Vincent H. J. van der Velden, Esther Mejstrikova, Josep-Maria Ribera, Valentino Conter, Martin Schrappe, Jacques J. M. van Dongen, Marcelo G. P. Land, Alberto Orfao
Summary: An imbalanced ratio of endothelial cells (EC) to mesenchymal stem cells (MSC) in the bone marrow at day +78 of therapy is associated with a shorter disease-free survival (DFS) in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients, independent of their measurable residual disease (MRD) status.
Article
Cell Biology
Mihaela Zlei, Igor A. Sidorov, Simone A. Joosten, Mirjam H. M. Heemskerk, Sebenzile K. Myeni, Cilia R. Pothast, Caroline S. de Brouwer, A. Linda Boomaars-van der Zanden, Krista E. van Meijgaarden, Shessy T. Morales, Els Wessels, Jacqueline J. Janse, Jelle J. Goeman, Christa M. Cobbaert, Aloys C. M. Kroes, Suzanne C. Cannegieter, Meta Roestenberg, Leonardus G. Visser, Marjolein Kikkert, Mariet C. W. Feltkamp, Sesmu M. Arbous, Frank J. T. Staal, Tom H. M. Ottenhoff, Jacques J. M. van Dongen, Anna H. E. Roukens, Jutte J. C. de Vries
Summary: This study highlights the importance of immune responses in determining disease severity and viral clearance after SARS-CoV-2 infection. Delayed viral clearance is associated with more severe disease, higher levels of neutralising antibodies, and ongoing immune activation. Early viral clearance and less critical illness are correlated with peak neutralising antibodies, higher levels of CD4 T cells, and particularly naive CD4+ T cells, suggesting their role in early control of the virus.
Article
Oncology
Marta E. Capala, Katrin S. Pachler, Iris Lauwers, Maarten A. de Korte, Nicole S. Verkaik, Hetty Mast, Brend P. Jonker, Aniel Sewnaik, Jose A. Hardillo, Stijn Keereweer, Dominiek Monserez, Senada Koljenovic, Bianca Mostert, Gerda M. Verduijn, Steven Petit, Dik C. van Gent
Summary: The study developed an assay to evaluate the response of head and neck tumor cells to radiation and chemotherapy. The results showed that different tumors had a varied reaction to treatment, with sensitive tumors showing partial DNA damage repair, decreased proliferation, and increased cell death, while resistant tumors were able to recover from treatment. The next step is to determine if these differences can predict treatment outcomes in a clinical trial.
Article
Immunology
Martijn Cordes, Kirsten Cante-Barrett, Erik B. van den Akker, Federico A. Moretti, Szymon M. Kielbasa, Sandra A. Vloemans, Laura Garcia-Perez, Cristina Teodosio, Jacques J. M. van Dongen, Karin Pike-Overzet, Marcel J. T. Reinders, Frank J. T. Staal
Summary: This study used a combination of single-cell techniques and functional assays to analyze the development of T cells in the human thymus. The researchers identified progenitor populations in the thymus that can also be found in the bone marrow. Additionally, they found that the human thymus supports the development of various immune cells, which is important for guiding regenerative therapies.
SCIENCE IMMUNOLOGY
(2022)
Article
Medicine, Research & Experimental
Annieck M. Diks, Hans de Graaf, Cristina Teodosio, Rick J. Groenland, Bas de Mooij, Muktar Ibrahim, Alison R. Hill, Robert C. Read, Jacques J. M. van Dongen, Magdalena A. Berkowska
Summary: This study used high-dimensional flow cytometry to monitor the cellular responses to Bordetella pertussis challenge in the blood of 15 healthy donors. The results showed that individuals protected against colonization exhibited different early cellular responses compared to colonized individuals. These early cellular immune responses can be further characterized and potentially linked to an efficient mucosal immune response, ultimately evaluating the protective efficacy of new B. pertussis vaccine candidates.
JOURNAL OF CLINICAL INVESTIGATION
(2023)