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
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
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
Biotechnology & Applied Microbiology
Jun-Liang Tu, Xin-Yuan Bai, Yong-Liang Xu, Na Li, Jun-Wei Xu
Summary: This study successfully inactivated the nonhomologous end-joining (NHEJ) pathway in Ganoderma lucidum using the CRISPR/Cas9 system, by disrupting the Ku70 gene, to establish an efficient tool for targeted gene insertion and replacement. Strains with disrupted ku70 gene exhibited high gene targeting efficiency, advancing our understanding of the functional genomics of G. lucidum.
APPLIED AND ENVIRONMENTAL MICROBIOLOGY
(2021)
Article
Oncology
Jennifer M. Geris, E. Susan Amirian, Deborah A. Marquez-Do, Martial Guillaud, Laura M. Dillon, Michele Follen, Michael E. Scheurer
Summary: This study investigates the association between HPV16 and HPV18 viral integration status and SNPs in nonhomologous-end-joining (NHEJ) DNA repair pathway genes on cervical dysplasia. The results show that SNPs in NHEJ DNA repair pathway genes, particularly XRCC4, are significantly associated with HPV integration, suggesting that these genes may play an important role in determining cervical cancer development and progression.
CANCER PREVENTION RESEARCH
(2023)
Article
Oncology
Nannan Guo, Shaojun Li, Bo Liu, Ping Chen, Jingbo Li, Yunlong Zhao, Yingnan Zhao, Jian Tang, Wen Zhang
Summary: The combination of Ku70/80 heterodimer protein inhibitor STL127705 and gemcitabine was found to enhance the sensitivity of NSCLC cell lines to irradiation and induce apoptosis. This combination treatment effectively inhibits the NHEJ pathway and enhances DNA damage, leading to tumor cell death.
Article
Cell Biology
Xiaojing Liu, Tingting Liu, Yafang Shang, Pengfei Dai, Wubing Zhang, Brian J. Lee, Min Huang, Dingpeng Yang, Qiu Wu, Liu Daisy Liu, Xiaoqi Zheng, Bo O. Zhou, Junchao Dong, Leng-Siew Yeap, Jiazhi Hu, Tengfei Xiao, Shan Zha, Rafael Casellas, X. Shirley Liu, Fei-Long Meng
Article
Multidisciplinary Sciences
Dingpeng Yang, Ying Sun, Jingjing Chen, Ying Zhang, Shuangshuang Fan, Min Huang, Xia Xie, Yanni Cai, Yafang Shang, Tuantuan Gui, Liming Sun, Jiazhi Hu, Junchao Dong, Leng-Siew Yeap, Xiaoming Wang, Wei Xiao, Fei-Long Meng
NATURE COMMUNICATIONS
(2020)
Article
Biochemistry & Molecular Biology
Qian Wang, Jin Liu, Josephine M. Janssen, Marie Le Bouteiller, Richard L. Frock, Manuel A. F. Goncalves
Summary: The study demonstrates that high-specificity Cas9 nucleases can be converted into nicking Cas9(D10A) variants with superior precision compared to the commonly used Cas9(D10A)nickase. Dual nicking RGNs based on these Cas9(D10A) variants can achieve gene knockouts and knock-ins at frequencies similar to or higher than conventional methods. Additionally, the high-specificity dual nicking RGNs are able to distinguish highly similar sequences and preserve genomic integrity.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Multidisciplinary Sciences
Zhuoyi Liang, Vipul Kumar, Marie Le Bouteiller, Jeffrey Zurita, Josefin Kenrick, Sherry G. Lin, Jiangman Lou, Jianqiao Hu, Adam Yongxin Ye, Cristian Boboila, Frederick W. Alt, Richard L. Frock
Summary: The study demonstrates that in Lig4-deficient G1-arrested progenitor B cells, Ku-dependent blockage of A-EJ leads to functional endjoining suppression. However, joining of RAG-generated DSBs in Ku70-deficient or Ku70/Lig4 double-deficient cells occurs through a translocation-like A-EJ mechanism.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Jiyu Tong, Xuefei Wang, Yongbo Liu, Xingxing Ren, Anmin Wang, Zonggui Chen, Jiameng Yao, Kaiqiong Mao, Tingting Liu, Fei-Long Meng, Wen Pan, Qiang Zou, Jun Liu, Yu Zhou, Qiang Xia, Richard A. Flavell, Shu Zhu, Hua-Bing Li
Summary: Research has identified the important role of METTL3-mediated m(6)A modification in host immune responses, regulating macrophage activation through the TLR signaling pathway. This may serve as a potential target for cancer immunotherapy.
Article
Cell Biology
Annalisa Lattanzi, Joab Camarena, Premanjali Lahiri, Helen Segal, Waracharee Srifa, Christopher A. Vakulskas, Richard L. Frock, Josefin Kenrick, Ciaran Lee, Narae Talbott, Jason Skowronski, M. Kyle Cromer, Carsten T. Charlesworth, Rasmus O. Bak, Sruthi Mantri, Gang Bao, David DiGiusto, John Tisdale, J. Fraser Wright, Neehar Bhatia, Maria Grazia Roncarolo, Daniel P. Dever, Matthew H. Porteus
Summary: This study demonstrated the preclinical feasibility, efficacy, and toxicology of HBB gene correction in CD34(+) cells from healthy and SCD patient donors. Up to 60% HBB allelic correction was achieved in clinical-scale gcHBB-SCD manufacturing, with 20% gene correction in immunodeficient NSG mice after transplant.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Oncology
Katsuhiro Togami, Sun Sook Chung, Vikas Madan, Christopher A. G. Booth, Christopher M. Kenyon, Lucia Cabal-Hierro, Justin Taylor, Sunhee S. Kim, Gabriel K. Griffin, Mahmoud Ghandi, Jia Li, Yvonne Y. Li, Fanny Angelot-Delettre, Sabeha Biichle, Michael Seiler, Silvia Buonamici, Scott B. Lovitch, Abner Louissaint, Elizabeth A. Morgan, Fabrice Jardin, Pier Paolo Piccaluga, David M. Weinstock, Peter S. Hammerman, Henry Yang, Marina Konopleva, Naveen Pemmaraju, Francine Garnache-Ottou, Omar Abdel-Wahab, H. Phillip Koeffler, Andrew A. Lane
Summary: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia primarily occurring in males, and the mutations in X chromosome gene ZRSR2 are associated with impaired dendritic cell function and predisposition to leukemic transformation.
Review
Biochemistry & Molecular Biology
Richard L. Frock, Cheyenne Sadeghi, Jodie Meng, Jing L. Wang
Summary: Humans have evolved multiple DNA double-strand break repair pathways, with NHEJ and A-EJ functioning in different cell cycle phases. While NHEJ is primarily utilized for covalent rejoining of DNA ends, A-EJ can also repair DSBs in the absence of NHEJ.
Article
Biochemistry & Molecular Biology
Xia Xie, Tingting Gan, Bing Rao, Weiwei Zhang, Rohit A. Panchakshari, Dingpeng Yang, Xiong Ji, Yu Cao, Frederick W. Alt, Fei-Long Meng, Jiazhi Hu
Summary: The mutant AID-delC protein fails to efficiently target antibody genes, forms condensates, and may exert a dominant-negative effect on wild-type AID.
Article
Environmental Sciences
Trevor R. Tivey, Tyler J. Coleman, Virginia M. Weis
Summary: The ability of symbionts to recolonize their hosts after a period of dysbiosis is essential for a resilient partnership. This study developed a non-invasive imaging method to measure symbiont abundance and distribution, and found that recolonization of symbionts in a sea anemone model followed a predictable cluster pattern. Native symbionts rapidly recolonized hosts and were more susceptible to bleaching under elevated temperature, while non-native symbionts persisted at low levels. The study suggests that colonization requires both localized proliferation and continuous migration.
FRONTIERS IN MARINE SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Jinglong Wang, Julien Le Gall, Richard L. Frock, Terence R. Strick
Summary: Using Sanger sequencing, high-throughput genome sequencing, and single-molecule experiments, the authors observe that the Streptococcus pyogenes SpCas9 complex generates overhanging DNA ends in response to internal mechanical strain. They also find that the dissociation of the complex and release of broken DNA ends are rate-limiting steps of the reaction.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Oncology
Paul G. Barghouth, Stavros Melemenidis, Pierre Montay-Gruel, Jonathan Ollivier, Vignesh Viswanathan, Patrik G. Jorge, Luis A. Soto, Brianna C. Lau, Cheyenne Sadeghi, Anushka Edlabadkar, Richard Zhang, Ning Ru, Janet E. Baulch, Rakesh Manjappa, Jinghui Wang, Marie Le Bouteiller, Murat Surucu, Amy Yu, Karl Bush, Lawrie Skinner, Peter G. Maxim, Billy W. Loo Jr, Charles L. Limoli, Marie-Catherine Vozenin, Richard L. Frock
Summary: The study aimed to investigate the effects of radiotherapy at different dose rates on DNA double strand breaks. The results showed that both ultra high dose rate and conventional dose rate radiotherapy produced chromosomal translocations, and the levels and structures were not significantly different from those produced by conventional dose rate radiotherapy.
RADIOTHERAPY AND ONCOLOGY
(2023)
Meeting Abstract
Oncology
Paul Barghouth, Jonathan Ollivier, Pierre Montay-Gruel, Billy W. Loo, Marie-Catherine Vozenin, Charles Limoli, Richard Frock
CLINICAL CANCER RESEARCH
(2021)
Article
Immunology
Xiaofei Ye, Weicheng Ren, Dongbing Liu, Xiaobo Li, Wei Li, Xianhuo Wang, Fei-Long Meng, Leng-Siew Yeap, Yong Hou, Shida Zhu, Rafael Casehs, Huilai Zhang, Kui Wu, Qiang Pan-Hammarstrom
Summary: Genomic analysis of DLBCL, FL, and chronic lymphocytic leukemia subtypes revealed different mutational signatures associated with AID activity. These mutational signatures can be linked to distinct developmental paths for different subtypes of B cell lymphomas.
JOURNAL OF EXPERIMENTAL MEDICINE
(2021)
Article
Multidisciplinary Sciences
Jingzheng Li, Yafang Shang, Lin Wang, Bo Zhao, Chunli Sun, Jiali Li, Siling Liu, Cong Li, Min Tang, Fei-Long Meng, Ping Zheng