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JOURNAL ARTICLE
Nagesh Kishan Panchal, Poorva Samdani, Tiasa Sengupta, Sabina Evan Prince
Ataxia telangiectasia-mutated (ATM) protein kinase, a key player in cellular integrity regulation, is known for its role in DNA damage response. This study investigates the broader impact of ATM on cellular processes and potential clinical manifestations arising from mutations, aiming to expand our understanding of ATM's diverse functions beyond conventional roles. The research employs a comprehensive set of computational techniques for a thorough analysis of ATM mutations. The mutation data are curated from dbSNP and HuVarBase databases...
March 15, 2024: Molecular Biotechnology
#22
JOURNAL ARTICLE
Weifeng Zhang, Gaocai Li, Xingyu Zhou, Huaizhen Liang, Bide Tong, Di Wu, Kevin Yang, Yu Song, Bingjin Wang, Zhiwei Liao, Liang Ma, Wencan Ke, Xiaoguang Zhang, Jie Lei, Chunchi Lei, Xiaobo Feng, Kun Wang, Kangcheng Zhao, Cao Yang
As the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socioeconomic challenge to the aging population and is largely attributed to intervertebral disc degeneration (IVDD). Elastic nucleus pulposus (NP) tissue is essential for the maintenance of IVD structural and functional integrity. The accumulation of senescent NP cells with an inflammatory hypersecretory phenotype due to aging and other damaging factors is a distinctive hallmark of IVDD initiation and progression. In this study, we reveal a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) axis but not of absent in melanoma 2 (AIM2) inflammasome assembly...
January 23, 2024: Journal of Clinical Investigation
#23
REVIEW
Dimitra Mavroeidi, Anastasia Georganta, Emmanouil Panagiotou, Konstantinos Syrigos, Vassilis L Souliotis
The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing a reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry, and mitotic catastrophe...
February 27, 2024: International Journal of Molecular Sciences
#24
JOURNAL ARTICLE
Siyuan Chen, Chen Pan, Jun Huang, Ting Liu
Upon replication fork stalling, the RPA-coated single-stranded DNA (ssDNA) formed behind the fork activates the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase, concomitantly initiating Rad18-dependent monoubiquitination of PCNA. However, whether crosstalk exists between these two events and the underlying physiological implications of this interplay remain elusive. In this study, we demonstrate that during replication stress, ATR phosphorylates human Rad18 at Ser403, an adjacent residue to a previously unidentified PIP motif (PCNA-interacting peptide) within Rad18...
March 11, 2024: EMBO Journal
#25
JOURNAL ARTICLE
Anitha Sokay, Timothy Ronan Leahy, Mary O'Regan, Michael O' Grady
Ataxia telangiectasia (A-T) (OMIM 208900) is an autosomal recessive multisystem disorder characterised by progressive cerebellar ataxia, telangiectasias, immunodeficiency and a predisposition to malignancy. 'Variant' A-T has later onset of neurological symptoms and slower progression compared with the 'classic' form. A woman presented with short stature in late childhood. Karyotype revealed rearrangements involving chromosomes 7 and 14. A chromosomal breakage disorder gene panel demonstrated compound heterozygote mutations in her ATM gene including one mutation c...
March 7, 2024: BMJ Case Reports
#26
JOURNAL ARTICLE
Phillip R Woolley, Xuemei Wen, Olivia M Conway, Nicolette A Ender, Ji-Hoon Lee, Tanya T Paull
The ataxia telangiectasia mutated (ATM) protein kinase is a master regulator of the DNA damage response and also an important sensor of oxidative stress. Analysis of gene expression in ataxia-telangiectasia (A-T) patient brain tissue shows that large-scale transcriptional changes occur in patient cerebellum that correlate with the expression level and guanine-cytosine (GC) content of transcribed genes. In human neuron-like cells in culture, we map locations of poly(ADP-ribose) and RNA-DNA hybrid accumulation genome-wide with ATM inhibition and find that these marks also coincide with high transcription levels, active transcription histone marks, and high GC content...
March 4, 2024: Cell Reports
#27
JOURNAL ARTICLE
Raul Alexander Gonzáles-Córdova, Thamires Rossi Dos Santos, Camila Gachet-Castro, Johnathan Andrade Vieira, Lays Adrianne Mendonça Trajano-Silva, Elza Tiemi Sakamoto-Hojo, Munira Muhammad Abdel Baqui
Trypanosoma cruzi, the etiological agent of Chagas disease, invades many cell types affecting numerous host-signalling pathways. During the T. cruzi infection, we demonstrated modulations in the host RNA polymerase II activity with the downregulation of ribonucleoproteins affecting host transcription and splicing machinery. These alterations could be a result of the initial damage to the host DNA caused by the presence of the parasite, however, the mechanisms are not well understood. Herein, we examined whether infection by T...
March 4, 2024: Scientific Reports
#28
JOURNAL ARTICLE
Hui Wang-Heaton, Mary C Wingard, Suman Dalal, Paige L Shook, Barbara A Connelly, Patrick Johnson, Phillip L Nichols, Mahipal Singh, Krishna Singh
AIMS: Published work has shown that ataxia-telangiectasia mutated kinase (ATM) deficiency is associated with cardioprotective effects in Western-type diet (WD)-fed female mice. This study assessed the expression of proteins related to fatty acid oxidation (FAO) and oxidative stress in WD-fed male and female mouse hearts, and investigated if sex-specific cardioprotective effects in WD-fed female ATM-deficient mice are maintained following myocardial infarction (MI). MAIN METHODS: Wild-type (WT) and ATM-deficient (hKO) mice (both sexes) were placed on WD for 14 weeks...
April 1, 2024: Life Sciences
#29
JOURNAL ARTICLE
Patrick G Pilie, Virginia Giuliani, Wei-Lien Wang, Daniel J McGrail, Christopher A Bristow, Natalie Y L Ngoi, Keith Kyewalabye, Khalida M Wani, Hung Le, Erick Campbell, Nora S Sánchez, Dong Yang, Jinesh S Gheeya, Rohit Vivek Goswamy, Vijaykumar Holla, Kenna Rael Shaw, Funda Meric-Bernstam, Chiu-Yi Liu, XiaoYan Ma, Ningping Feng, Annette A Machado, Jennifer P Bardenhagen, Christopher P Vellano, Joseph R Marszalek, Eeson Rajendra, Desiree Piscitello, Timothy I Johnson, Maria Likhatcheva, Elias Elinati, Jayesh Majithiya, Joana Neves, Vera Grinkevich, Marco Ranzani, Marina Roy-Luzarraga, Marie Boursier, Lucy Armstrong, Lerin Geo, Giorgia Lillo, Wai Yiu Tse, Alexander J Lazar, Scott E Kopetz, Mary K Geck Do, Sarah Lively, Michael G Johnson, Helen M R Robinson, Graeme C M Smith, Christopher L Carroll, M Emilia Di Francesco, Philip Jones, Timothy P Heffernan, Timothy A Yap
PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors, and then assessed the ATM variant-to-protein relationship...
February 28, 2024: Clinical Cancer Research
#30
Gonzalo Lendinez-Sanchez, Tamara Diaz-Redondo, Marcos Iglesias Campos, Javier Porta Pelayo, José María Porta Pelayo, Carolina Muriel-López
INTRODUCTION: Ataxia-Telangiectasia Mutated (ATM) is a cancer predisposition gene; carriers of germline pathogenic variants have an increased risk of developing malignancies, including breast, prostate, pancreatic, and ovarian cancer. Most ATM variants are of uncertain significance. Findings from genome-wide association studies (GWAS) suggest that ATM may be a low-risk melanoma susceptibility locus. CASE REPORT: We report the case of a Hispanic family whose members who have presented cutaneous melanoma have been found to be carriers for the ATM pathogenic variant c...
2024: Case Reports in Oncology
#31
JOURNAL ARTICLE
Qi-Zhang Li, Yu-Ying Chen, Qiu-Ping Liu, Zhi-Hui Feng, Lei Zhang, Hong Zhang
BACKGROUND: The mortality rate of liver cancer ranks third in the world, and hepatocellular carcinoma (HCC) is a malignant tumor of the digestive tract. Cucurbitacin B (CuB), a natural compound extracted from Cucurbitaceae spp., is the main active component of Chinese patent medicine the Cucurbitacin Tablet, which has been widely used in the treatment of various malignant tumors in clinics, especially HCC. PURPOSE: This study explored the role and mechanism of CuB in the suppression of liver cancer progression...
April 2024: Phytomedicine
#32
JOURNAL ARTICLE
Timothy A Yap, Anthony W Tolcher, Ruth Plummer, Jatinder Kaur Mukker, Marta Enderlin, Christine Hicking, Thomas Grombacher, Giuseppe Locatelli, Zoltan Szucs, Ioannis Gounaris, Johann S de Bono
PURPOSE: Tuvusertib (M1774) is a potent, selective, orally administered ATR protein kinase inhibitor. This first-in-human study (NCT04170153) evaluated safety, tolerability, maximum tolerated dose (MTD), recommended dose for expansion (RDE), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of tuvusertib monotherapy. PATIENTS AND METHODS: Ascending tuvusertib doses were evaluated in 55 patients with metastatic or locally advanced unresectable solid tumors...
February 26, 2024: Clinical Cancer Research
#33
JOURNAL ARTICLE
Zun-Hong Liang, Shi-Shuai Lin, Zhi-Yang Qiu, Yun-Chuan Pan, Nan-Fang Pan, Yun Liu
Diabetic foot ulcer (DFU) is a serious complication of diabetic patients which negatively affects their foot health. This study aimed to estimate the role and mechanism of the miR-200 family in DNA damage of diabetic wound healing. Human foreskin fibroblasts (HFF-1 cells) were stimulated with high glucose (HG). Db/db mice were utilized to conduct the DFU in vivo model. Cell viability was evaluated using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assays. Superoxide dismutase activity was determined using detection kits...
February 22, 2024: Kaohsiung Journal of Medical Sciences
#34
JOURNAL ARTICLE
Syeda Anjum Mobeen, Pallavi Saxena, Arun Kumar Jain, Ravi Deval, Khateef Riazunnisa, Dibyabhaba Pradhan
BACKGROUND: Colorectal cancer (CRC) is the fifth leading cause of death in India. Until now, the exact pathogenesis concerning CRC signaling pathways is largely unknown; however, the diseased condition is believed to deteriorate with lifestyle, aging, and inherited genetic disorders. Hence, the identification of hub genes and therapeutic targets is of great importance for disease monitoring. OBJECTIVE: Identification of hub genes and targets for identification of candidate hub genes for CRC diagnosis and monitoring...
October 1, 2023: Journal of Cancer Research and Therapeutics
#35
JOURNAL ARTICLE
Nigel S Michki, Benjamin D Singer, Javier V Perez, Aaron J Thomas, Valerie Natale, Kathryn A Helmin, Jennifer Wright, Leon Cheng, Lisa R Young, Howard M Lederman, Sharon A McGrath-Morrow
INTRODUCTION: Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In this study, we sought to determine whether transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) defines subsets of individuals with A-T beyond mild and classic phenotypes, enabling identification of novel features for disease classification and treatment response to therapy. METHODS: Participants with classic A-T (n = 77), mild A-T (n = 13), and unaffected controls (n = 15) were recruited from two outpatient clinics...
February 14, 2024: Orphanet Journal of Rare Diseases
#36
JOURNAL ARTICLE
Zhenbang Gu, Peng Huang, Jiali Zhao, Chen Luo, Lingmin Liao, Anwen Liu, Long Huang
Bilateral diffuse metastatic lung adenocarcinoma (BLDM-LUAD) is a special imaging pattern of lung adenocarcinoma (LUAD). We retrospectively assessed survival outcomes and co-mutation characteristics of BLDM-LUAD patients harboring epidermal growth factor receptor (EGFR) mutations who were treated with EGFR-yrosine kinase inhibitors (TKIs). From May 2016 to May 2021, among 458 patients who submitted samples for next generation sequencing (NGS) detection in 1125 patients with non-small-cell lung cancer (NSCLC), and 44 patients were diagnosed as BLDM-LUAD...
June 1, 2024: International Journal of Cancer. Journal International du Cancer
#37
JOURNAL ARTICLE
Onyisi Christiana Didamson, Rahul Chandran, Heidi Abrahamse
INTRODUCTION: Photodynamic therapy (PDT) is a light-based technique used in the treatment of malignant and non-malignant tissue. Aluminium-phthalocyanine chloride tetra sulfonate (AlPcS4Cl)-mediated PDT has been well investigated on several cancer types, including oesophageal cancer. However, the effects of (AlPcS4Cl)-mediated PDT on DNA damage response and the mechanism of cell death in oesophageal cancer needs further investigation. METHODS: Here, we examined the in vitro effects of AlPcS4 Cl-mediated PDT on cell cycle, DNA damage response, oxidative stress, and intrinsic apoptotic cell death pathway in HKESC-1 oesophageal cancer cells...
2024: Frontiers in Oncology
#38
JOURNAL ARTICLE
Caroline Atkinson, Aideen M McInerney-Leo, Martina Proctor, Catherine Lanagan, Alexander J Stevenson, Farhad Dehkhoda, Mary Caole, Ellie Maas, Stephen Ainger, Antonia L Pritchard, Peter A Johansson, Paul Leo, Nicholas K Hayward, Richard A Sturm, Emma L Duncan, Brian Gabrielli
An apical component of the cell cycle checkpoint and DNA damage repair response is the ataxia-telangiectasia mutated (ATM) Ser/Thr protein kinase. A variant of ATM, Ser49Cys (rs1800054; minor allele frequency = 0.011), has been associated with an elevated risk of melanoma development; however, the functional consequence of this variant is not defined. ATM-dependent signalling in response to DNA damage has been assessed in a panel of patient-derived lymphoblastoid lines and primary human melanocytic cell strains heterozygous for the ATM Ser49Cys variant allele...
January 29, 2024: International Journal of Molecular Sciences
#39
JOURNAL ARTICLE
Amir-Reza Dalal Amandi, Neda Jabbarpour, Shadi Shiva, Mortaza Bonyadi
BACKGROUND: The ATM gene encodes a multifunctional kinase involved in important cellular functions, such as checkpoint signaling and apoptosis, in response to DNA damage. Bi-allelic pathogenic variants in this gene cause Ataxia Telangiectasia (AT), while carriers of ATM pathogenic variants are at increased risk of cancer depending on the pathogenicity of the variant they carry. Identifying pathogenic variants can aid in the management of the disease in carriers. METHODS: Whole-exome sequencing (WES) was performed on three unrelated patients from the Iranian-Azeri Turkish ethnic group referred to a genetic center for analysis...
December 28, 2023: Current Genomics
#40
JOURNAL ARTICLE
Jovanka Vladejić, Martin Kovacik, Jana Zwyrtková, Miriam Szurman-Zubrzycka, Jaroslav Doležel, Ales Pecinka
DNA damage response (DDR) is an essential mechanism by which living organisms maintain their genomic stability. In plants, DDR is important also for normal growth and yield. Here, we explored the DDR of a temperate model crop barley (Hordeum vulgare) at the phenotypic, physiological, and transcriptomic levels. By a series of in vitro DNA damage assays using the DNA strand break (DNA-SB) inducing agent zeocin, we showed reduced root growth and expansion of the differentiated zone to the root tip. Genome-wide transcriptional profiling of barley wild-type and plants mutated in DDR signaling kinase ATAXIA TELANGIECTASIA MUTATED AND RAD3-RELATED (hvatr...
February 7, 2024: Scientific Reports
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