Review
Immunology
Holly Wobma, Daniel S. Shin, Janet Chou, Fatma Dedeoglu
Summary: Detection of foreign DNA is one of the oldest immune defense mechanisms against pathogens, and the cGAS-STING pathway plays a crucial role in this process. While physiologic levels of STING signaling are protective, chronic activation of this pathway can lead to autoinflammation and autoimmunity. This article discusses monogenic disorders of the STING pathway and its impact on innate and adaptive immunity, as well as its potential relevance in systemic lupus erythematosus and future monitoring and targeting approaches.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Immunology
Alice Lepelley, Erika Della Mina, Erika Van Nieuwenhove, Lise Waumans, Sylvie Fraitag, Gillian I. Rice, Ashish Dhir, Marie-Louise Fremond, Mathieu P. Rodero, Luis Seabra, Edwin Carter, Christine Bodemer, Daniela Buhas, Bert Callewaert, Pascale de Lonlay, Lien De Somer, David A. Dyment, Fran Faes, Lucy Grove, Simon Holden, Marie Hully, Manju A. Kurian, Hugh J. McMillan, Kristin Suetens, Henna Tyynismaa, Stephanie Chhun, Timothy Wai, Carine Wouters, Brigitte Bader-Meunier, Yanick J. Crow
Summary: Mutations in the mitochondrial membrane protein ATAD3A lead to enhanced interferon signaling, resulting in a novel type I interferonopathy. Knockdown of ATAD3A can suppress interferon signaling. This sheds light on the role of mitochondrial membrane protein ATAD3A in immune system activation.
JOURNAL OF EXPERIMENTAL MEDICINE
(2021)
Article
Multidisciplinary Sciences
Ze Hong, Jiahao Mei, Chenhui Li, Guohui Bai, Munire Maimaiti, Haiyang Hu, Wenying Yu, Li Sun, Lele Zhang, Dan Cheng, Yixian Liao, Senlin Li, Yanping You, Hongbin Sun, Jing Huang, Xing Liu, Judy Lieberman, Chen Wang
Summary: A potent STING antagonist SN-011 has been identified through in silico docking, which locks STING in an open inactive conformation and inhibits interferon and inflammatory cytokine induction. This specific STING inhibitor shows promising potential for treating STING-driven autoimmune diseases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Health Care Sciences & Services
Marta Swierczynska, Agnieszka Tronina, Erita Filipek
Summary: This study reports a case of AGS with less common ocular involvement, including congenital glaucoma. The diagnosis of AGS1 was confirmed through clinical, electrophysiological, imaging, and genetic testing, and the association of TREX1 gene mutations with ocular complications was expanded.
JOURNAL OF PERSONALIZED MEDICINE
(2023)
Article
Chemistry, Multidisciplinary
Leonard Barasa, Sauradip Chaudhuri, Jeffrey Y. Zhou, Zhaozhao Jiang, Shruti Choudhary, Robert Madison Green, Elenore Wiggin, Michael Cameron, Fiachra Humphries, Katherine A. Fitzgerald, Paul R. Thompson
Summary: The cGMP-AMP Synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway is crucial for detecting cytosolic dsDNA and triggering inflammatory response. Aberrant STING activation is associated with diseases such as ALS, lupus, AGS, and SAVI. In this study, we developed LB244 as a highly potent and selective inhibitor of STING signaling, which showed efficacy comparable to BB-Cl-amidine in vivo. These findings suggest a potential therapeutic approach for STING-dependent inflammatory diseases.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Evolutionary Biology
Sabateeshan Mathavarajah, Andrew W. Thompson, Matthew R. Stoyek, T. Alexander Quinn, Stephane Roy, Ingo Braasch, Graham Dellaire
Summary: This study reveals that aquatic vertebrates undergo transcriptional rewiring of innate immune signaling pathways during limb and fin regeneration to promote immune cell recruitment. The study also shows that cGAS-STING pathway and various suppressors of cytosolic DNA play important roles in the regeneration process. The findings provide insights into the molecular mechanisms behind tissue regeneration in aquatic animals.
JOURNAL OF EXPERIMENTAL ZOOLOGY PART B-MOLECULAR AND DEVELOPMENTAL EVOLUTION
(2023)
Article
Biochemistry & Molecular Biology
Iman Al Khatib, Jingti Deng, Yuanjiu Lei, Sylvia Torres-Odio, Gladys R. Rojas, Laura E. Newman, Brian K. Chung, Andrew Symes, Hongliang Zhang, Shar-yin N. Huang, Yves Pommier, Aneal Khan, Gerald S. Shadel, Andrew Phillip West, William T. Gibson, Timothy E. Shutt
Summary: The discovery of the P193L variant in TOP1MT, which affects its function, in a family with multiple autoimmune diseases, including SLE, highlights the role of TOP1MT in regulating the release of mitochondrial DNA and activating the cGAS-STING pathway.
HUMAN MOLECULAR GENETICS
(2023)
Article
Multidisciplinary Sciences
Hekang Du, Nanyang Xiao, Sitong Zhang, Xueyuan Zhou, Yangfan Zhang, Zengzeng Lu, Yuqian Fu, Miaohui Huang, Shan Xu, Qi Chen
Summary: Mutations in the TREX1 gene can lead to cellular senescence and contribute to the development of type I interferonopathies and lupus-like diseases. This study identifies the involvement of DNA damage and the cGAS-STING and DNA damage response pathways in cellular senescence induced by TREX1 deletion. Inhibition of the DNA damage response can partially alleviate disease progression and may guide the development of targeted therapeutics.
Article
Biochemistry & Molecular Biology
Sabateeshan Mathavarajah, Kathleen L. Vergunst, Elias B. Habib, Shelby K. Williams, Raymond He, Maria Maliougina, Mika Park, Jayme Salsman, Stephane Roy, Ingo Braasch, Andrew J. Roger, David N. Langelaan, Graham Dellaire
Summary: We have discovered that the PML gene and novel PML-like DEDDh exonucleases play a vital role in maintaining genome stability by restricting L1 retrotransposition in jawed vertebrates. Unlike mammalian PML proteins that form nuclear bodies, the PML ortholog in spotted gar and related fish proteins function as cytoplasmic DEDDh exonucleases. In addition, we identified Plex9 genes in teleost fishes that encode exonucleases similar to TREX1. These proteins not only suppressed L1 retrotransposition but also complemented TREX1 knockout in mammalian cells.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biotechnology & Applied Microbiology
Zhourui Ma, Qianwei Xiong, Hongliang Xia, Wei Liu, Shu Dai, Shizhong Cai, Zhenhong Zhu, Xiangming Yan
Summary: The study demonstrated that carboplatin activates TREX1 and cGAS/STING pathways to promote apoptosis and inhibit proliferation in human melanoma cells. Overexpression of TREX1 induced apoptosis and decreased proliferation, offering a new therapeutic strategy for melanoma treatment.
Article
Genetics & Heredity
Giulia Amico, Wayne O. Hemphill, Mariasavina Severino, Claudio Moratti, Rosario Pascarella, Marta Bertamino, Flavia Napoli, Stefano Volpi, Francesca Rosamilia, Sara Signa, Fred Perrino, Marialuisa Zedde, Isabella Ceccherini
Summary: This study reports the clinical-neuroradiological features of two patients with AGS-like and CADASIL-like phenotypes carrying respective TREX1 variants. Genetic findings, interferon signature testing, and biochemical assays were used to determine the effects of the variants in vitro. The results showed differences in enzymatic activity and impact on patient phenotypes between the p.A136V and p.R174G variants.
Article
Clinical Neurology
Salam Alburaiky, Russell C. Dale, Yanick J. Crow, Hannah F. Jones, Evangeline Wassmer, Isabelle Melki, Odile Boespflug-Tanguy, Jeremy Do Cao, Domitille Gras, Cynthia Sharpe
Summary: Aicardi-Goutieres syndrome (AGS) is a rare genetic neuroinflammatory disorder associated with Opsoclonus-myoclonus syndrome. Cases suggest that AGS should be considered in children presenting with opsoclonus-myoclonus, and a positive response to JAK1/2 inhibition was observed in two patients.
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY
(2021)
Article
Multidisciplinary Sciences
Nobuo Kanazawa, Hiroaki Hemmi, Noriko Kinjo, Hidenori Ohnishi, Jun Hamazaki, Hiroyuki Mishima, Akira Kinoshita, Tsunehiro Mizushima, Satoru Hamada, Kazuya Hamada, Norio Kawamoto, Saori Kadowaki, Yoshitaka Honda, Kazushi Izawa, Ryuta Nishikomori, Miyuki Tsumura, Yusuke Yamashita, Shinobu Tamura, Takashi Orimo, Toshiya Ozasa, Takashi Kato, Izumi Sasaki, Yuri Fukuda-Ohta, Naoko Wakaki-Nishiyama, Yutaka Inaba, Kayo Kunimoto, Satoshi Okada, Takeshi Taketani, Koichi Nakanishi, Shigeo Murata, Koh-ichiro Yoshiura, Tsuneyasu Kaisho
Summary: Genetic variants of the PSMB9 gene can cause autoinflammatory/immune deficiency syndrome, with impaired proteasome activity and maturation, leading to distinct symptoms such as pulmonary hypertension in addition to classic autoinflammatory syndromes. A mouse model of this genetic variant replicates the proteasome defects and immunodeficiency observed in patients, highlighting the importance of proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID) as a separate disease category.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Hong Sun, Yu Huang, Shan Mei, Fengwen Xu, Xiaoman Liu, Fei Zhao, Lijuan Yin, Di Zhang, Liang Wei, Chao Wu, Shichao Ma, Jianwei Wang, Shan Cen, Chen Liang, Siqi Hu, Fei Guo
Summary: cGAS is localized in both the cytoplasm and nucleus, demonstrating a functional nuclear export signal for its positioning between the nucleus and cytoplasm. Mutation of the key amino acid L172 results in the loss of interferon response to DNA stimulation.
Article
Genetics & Heredity
Kiwon Park, Jeongmin Ryoo, Heena Jeong, Minsu Kim, Sungwon Lee, Sung-Yeon Hwang, Jiyoung Ahn, Doyeon Kim, Hyungseok C. Moon, Daehyun Baek, Kwangsoo Kim, Hye Yoon Park, Kwangseog Ahn
Summary: Mutations in SAMHD1 gene are a cause of Aicardi-Goutieres syndrome and are also associated with various types of tumors and malignancies. SAMHD1 resolves R-loops induced by transcription-replication conflicts, contributing to genome stability maintenance. Depletion of SAMHD1 leads to R-loop accumulation and DNA damage responses, while downregulation of SAMHD1 expression is linked to different cancer types and poor survival rate. Thus, SAMHD1 and R-loop may serve as novel diagnostic markers and targets in anti-cancer therapy.
Article
Ethics
Landon J. Getz, Graham Dellaire
SCIENCE AND ENGINEERING ETHICS
(2020)
Article
Evolutionary Biology
Sabateeshan Mathavarajah, Graham Dellaire
EVOLUTION MEDICINE AND PUBLIC HEALTH
(2020)
Article
Biology
Jonghwa Lee, Jayme Salsman, Jason Foster, Graham Dellaire, Neale D. Ridgway
LIFE SCIENCE ALLIANCE
(2020)
Article
Biochemistry & Molecular Biology
Sabateeshan Mathavarajah, Carter VanIderstine, Graham Dellaire, Robert J. Huber
Summary: The model organism Dictyostelium discoideum provides insights into the evolution of unicellularity and multicellularity, aiding in the understanding of cancer-related gene networks. During development, Dictyostelium discoideum can form spore masses and stalk cells, with some cells sacrificing themselves. Cheating behaviors disrupt multicellularity principles and affect cell fate.
Article
Environmental Sciences
Sabateeshan Mathavarajah, Amina K. Stoddart, Graham A. Gagnon, Graham Dellaire
Summary: The ongoing COVID-19 pandemic has impacted public health, the economy, and society globally, with implications for the environment and wildlife. Poor wastewater management may lead to marine mammals being susceptible to infection by the SARS-CoV-2 virus through untreated wastewater discharge into natural water systems. Measures should be taken to prevent virus spillover in natural water systems to protect vulnerable marine wildlife populations.
SCIENCE OF THE TOTAL ENVIRONMENT
(2021)
Review
Genetics & Heredity
Kateryna Kratzer, Landon J. Getz, Thibaut Peterlini, Jean-Yves Masson, Graham Dellaire
Summary: Gene therapy for genetic diseases has gained increased attention, but faces technical challenges and ethical barriers. Current research is primarily focused on improving gene therapy and gene editing techniques, with less emphasis on the timing and rationale for using such technology.
Review
Cell Biology
J. P. Jose Merlin, H. P. Vasantha Rupasinghe, Graham Dellaire, Kieran Murphy
Summary: Cancer prevention and treatment involve multiple factors, including genetics, diet, DNA damage, and cell cycle regulation. Certain dietary components such as flavonoids and polyphenols can inhibit cancer progression through p53-mediated mechanisms. In addition, vitamins such as folic acid also play a significant role in chemoprevention.
OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
(2021)
Review
Genetics & Heredity
Elias Habib, Allyson Cook, Sabateeshan Mathavarajah, Graham Dellaire
Summary: Autophagy is a crucial pathway for cellular homeostasis, with ESCRT proteins and alternative pre-mRNA splicing playing important roles in regulating this process. Dysfunction in these mechanisms can lead to impaired cellular stress response or trigger pathogenic reactions, ultimately contributing to human diseases.
Article
Oncology
Brianne M. Cruickshank, Marie-Claire D. Wasson, Justin M. Brown, Wasundara Fernando, Jaganathan Venkatesh, Olivia L. Walker, Fiorella Morales-Quintanilla, Margaret L. Dahn, Dejan Vidovic, Cheryl A. Dean, Carter VanIderstine, Graham Dellaire, Paola Marcato
Summary: This study demonstrates that lncRNA PART1 is enriched in triple-negative breast cancers and cancer stem cells, and is associated with worse outcomes in some breast cancer patients. PART1 alters the miRNA landscape, leading to genome-wide mRNA expression regulation, making it an attractive target for the treatment of triple-negative breast cancers.
Article
Biochemistry & Molecular Biology
Livia E. Clarke, Allyson Cook, Sabateeshan Mathavarajah, Amit Bera, Jayme Salsman, Elias Habib, Carter Van Iderstine, Moamen Bydoun, Stephen M. Lewis, Graham Dellaire
Summary: PRP4K is an essential gene that when reduced is associated with aggressive breast and ovarian cancer phenotypes, leading to increased cell migration and invasion. These effects suggest that PRP4K functions as a haploinsufficient tumor suppressor.
Article
Biochemistry & Molecular Biology
J. P. Jose Merlin, Graham Dellaire, Kieran Murphy, H. P. Vasantha Rupasinghe
Summary: Lung cancer has the highest mortality rate globally and is often diagnosed at late stages, necessitating genotoxic chemotherapy. Cancer prevention, including the use of antioxidants, is a major focus. The study found that an antioxidant formulation has the potential to reduce DNA damage, showing promise as a chemoprotectant by attenuating activation of kinase following carcinogen exposure.
Review
Genetics & Heredity
Elias B. Habib, Sabateeshan Mathavarajah, Graham Dellaire
Summary: Pre-mRNA processing factor 4 kinase (PRP4K) is a conserved kinase that plays important roles in spliceosomal assembly. However, recent studies have revealed that PRP4K is also involved in various cellular pathways, including transcription regulation, spindle assembly checkpoint, and tumor suppression, contributing to tumorigenesis and chemotherapy response.
FRONTIERS IN GENETICS
(2022)
Article
Biochemistry & Molecular Biology
Tharindu L. Suraweera, J. P. Jose Merlin, Graham Dellaire, Zhaolin Xu, H. P. Vasantha Rupasinghe
Summary: Cancer is a leading cause of death globally, but current treatments like chemotherapy and radiation therapy have significant side effects. Therefore, the prevention of cancer through dietary modifications has gained interest. This study examined the potential of selected flavonoids in reducing reactive oxygen species (ROS) and DNA damage induced by carcinogens through the activation of the Nrf2/ARE pathway. The results showed that genistein and PCB2 could effectively reduce ROS and DNA damage, and further research is needed to understand the role of dietary flavonoids in regulating the Nrf2/ARE pathway in carcinogenesis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Evolutionary Biology
Sabateeshan Mathavarajah, Andrew W. Thompson, Matthew R. Stoyek, T. Alexander Quinn, Stephane Roy, Ingo Braasch, Graham Dellaire
Summary: This study reveals that aquatic vertebrates undergo transcriptional rewiring of innate immune signaling pathways during limb and fin regeneration to promote immune cell recruitment. The study also shows that cGAS-STING pathway and various suppressors of cytosolic DNA play important roles in the regeneration process. The findings provide insights into the molecular mechanisms behind tissue regeneration in aquatic animals.
JOURNAL OF EXPERIMENTAL ZOOLOGY PART B-MOLECULAR AND DEVELOPMENTAL EVOLUTION
(2023)
