Review
Cell Biology
Venturina Stagni, Alessandra Ferri, Claudia Cirotti, Daniela Barila
Summary: There is a strong interplay between autophagy and genomic stability, with recent evidence linking DNA Damage Response (DDR) and autophagy in influencing cell fate. ATM kinase plays a crucial role in balancing senescence and apoptosis in response to stimuli, and its aberrant deregulation is linked to the development of pathologies like cancer and neurodegeneration.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Cell Biology
Maria Likhatcheva, Roben G. Gieling, James A. L. Brown, Constantinos Demonacos, Kaye J. Williams
Summary: Genotoxic stress can activate the ATM kinase, with potential involvement of Suv39H1 and Tip60 in ATM activation under hypoxic conditions.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Genetics & Heredity
Mohammad Z. Islam, Xinggui Shen, Sibile Pardue, Christopher B. Pattillo, Christopher G. Kevil, Rodney E. Shackelford
Summary: The ATM protein plays a crucial role in regulating cell cycle checkpoints, cellular redox state, and DNA repair. Its loss in ataxia-telangiectasia (A-T) leads to symptoms such as ataxia, telangiectasias, dysregulated redox and iron responses, and increased cancer risk. Our study reveals that ATM regulates the sulfur pool, Fe-S cluster biosynthesis, transsulfuration pathway, and glutathione redox cycling, which may explain some of the redox- and iron-related pathologies seen in A-T.
Article
Immunology
Geraldine Blanchard-Rohner, Anna Peirolo, Ludivine Coulon, Christian Korff, Judit Horvath, Pierre R. Burkhard, Fabienne Gumy-Pause, Emmanuelle Ranza, Peter Jandus, Harpreet Dibra, Alexander Malcolm R. Taylor, Joel Fluss
Summary: Ataxia-telangiectasia (A-T) is a neurodegenerative and primary immunodeficiency disorder characterized by various symptoms. This study presents a case series highlighting the phenotypic variability of A-T and emphasizes the importance of early diagnosis of variant A-T and classical A-T.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Cell Biology
Julio Aguado, Cecilia Gomez-Inclan, Hannah C. Leeson, Martin F. Lavin, Yosef Shiloh, Ernst J. Wolvetang
Summary: Ataxia-telangiectasia (A-T) is a complex disorder characterized by progressive cerebellar degeneration, immunodeficiency, radiation sensitivity, genome instability, and predisposition to cancer. The premature aging component of A-T is of great importance in driving the disease.
AGEING RESEARCH REVIEWS
(2022)
Article
Biochemistry & Molecular Biology
Sapir Schlam-Babayov, Ariel Bensimon, Michal Harel, Tamar Geiger, Ruedi Aebersold, Yael Ziv, Yosef Shiloh
Summary: This study conducted a comprehensive phosphoproteomic analysis in human wild-type and A-T cells to reveal the fine-tuned dynamics and relationships between PIKKs in the response to genotoxic stress. The results highlight the complex interactions among ATM, ATR, and DNA-PK in the DDR.
Article
Immunology
Ruth Pia Duecker, Lucia Gronau, Patrick C. Baer, Stefan Zielen, Ralf Schubert
Summary: Our study focused on investigating the feasibility of different approaches of hematopoietic stem cell transplantation (HSCT) for Ataxia-telangiectasia (A-T) by using Atm-deficient mice as models. The results showed that haploidentical HSCT could extend the lifespan of Atm-deficient mice and improve T-cell numbers and functionality. Interestingly, HSCT using heterozygous donor cells also led to improved survival and enhanced CD4 cell functionality in Atm-deficient mice, suggesting it as a potential strategy for A-T treatment.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Mohammad Z. Islam, Rodney E. Shackelford
Summary: In this study, it was found that pioglitazone increased the levels of iron-sulfur clusters and protein bound sulfides, and reduced cystathionine gamma-lyase enzymatic activity. These effects were beneficial in cells with deficient ATM protein signaling.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Cell Biology
Majd Haj, Amit Levon, Yann Frey, Noa Hourvitz, Judith Campisi, Yehuda Tzfati, Ran Elkon, Yael Ziv, Yosef Shiloh
Summary: The genetic disorder A-T is caused by loss of the homeostatic protein kinase ATM and leads to genome instability, tissue degeneration, cancer predisposition, and premature aging. Lowering the oxygen concentration to a physiological level range significantly extends the proliferative lifespan of A-T fibroblasts, but they still undergo premature senescence and exhibit high genome instability. Senescing A-T fibroblasts show distinct transcriptional dynamics, including activation of interferon-stimulated genes and altered expression of genes associated with extracellular matrix remodeling.
Article
Cell Biology
Beimeng Yang, Xiuli Dan, Yujun Hou, Jong-Hyuk Lee, Noah Wechter, Sudarshan Krishnamurthy, Risako Kimura, Mansi Babbar, Tyler Demarest, Ross McDevitt, Shiliang Zhang, Yongqing Zhang, Mark P. Mattson, Deborah L. Croteau, Vilhelm A. Bohr
Summary: The study shows that mitochondrial dysfunction and cellular senescence occur in A-T patient fibroblasts, ATM-deficient cells, and mice, and boosting intracellular NAD(+) levels can prevent senescence and senescence-associated secretory phenotype (SASP) by promoting mitophagy in a PINK1-dependent manner. This suggests a central role for mitochondrial dysfunction-induced senescence in A-T pathogenesis and highlights enhancing mitophagy as a potential therapeutic intervention.
Article
Chemistry, Medicinal
Teodor Dimitrov, Cetin Anli, Athina Anastasia Moschopoulou, Thales Kronenberger, Mark Kudolo, Christian Geibel, Martin Peter Schwalm, Stefan Knapp, Lars Zender, Michael Forster, Stefan Laufer
Summary: A novel urea-based ATM kinase inhibitor was designed using in silico modeling, showing subnanomolar potency and excellent selectivity profile and metabolic stability in cellular models.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Allergy
Ismail Ogulur, Tugce Ertuzun, Burcu Kocamis, Yasemin Kendir Demirkol, Emel Uyar, Ayca Kiykim, Dilek Baser, Gozde Yesil, Hacer Akturk, Ayper Somer, Ahmet Ozen, Elif Karakoc-Aydiner, Meltem Muftuoglu, Safa Baris
Summary: Heterozygous relatives of ataxia-telangiectasia (AT) patients are at increased risk for certain AT-related manifestations, and parents of AT patients show an increase in infection frequency. It is hypothesized that parents may exhibit immune alterations similar to their affected children.
PEDIATRIC ALLERGY AND IMMUNOLOGY
(2021)
Article
Oncology
Michael J. Hall, Ryan Bernhisel, Elisha Hughes, Katie Larson, Eric T. Rosenthal, Nanda A. Singh, Johnathan M. Lancaster, Allison W. Kurian
Summary: This study estimated cancer risks associated with ATM pathogenic variants independently of family history, showing that some variants may have higher breast cancer risks than previously recognized. Increased screening for prostate and gastric cancer may be warranted for carriers of ATM pathogenic variants.
CANCER PREVENTION RESEARCH
(2021)
Article
Oncology
Madeline B. Torres, Laurence P. Diggs, Jun S. Wei, Javed Khan, Markku Miettinen, Grace-Ann Fasaye, Andy Gillespie, Brigitte C. Widemann, Rosandra N. Kaplan, Jeremy L. Davis, Jonathan M. Hernandez, Jaydira Del Rivero
Summary: Adrenocortical carcinoma (ACC) is a rare malignancy originating from the adrenal cortex, and surgery is currently the only curative option. This study reports a pathogenic variant in the ATM gene in a patient with ACC, suggesting a potential pathogenic role of ATM gene in certain ACC cases.
Review
Biochemistry & Molecular Biology
Laura A. Huff, Shan Yan, Mark G. Clemens
Summary: Cells have evolved extensive signaling mechanisms to maintain redox homeostasis, with a critical role of oxidants in normal signaling. However, excessive oxidants can lead to elevated oxidative stress, causing alterations in cellular operations and damage to cellular components. The cellular response to oxidative stress includes redox sensors that regulate the DNA damage response and orchestrated changes to the epigenome, protecting and regulating the nuclear genome.
Article
Biochemistry & Molecular Biology
Sara Sepe, Francesca Rossiello, Valeria Cancila, Fabio Iannelli, Valentina Matti, Giada Cicio, Matteo Cabrini, Eugenia Marinelli, Busola R. Alabi, Alessia di Lillo, Arianna Di Napoli, Jerry W. Shay, Claudio Tripodo, Fabrizio d'Adda di Fagagna
Summary: As individuals age, the expression of ACE2 in the lungs increases, making elderly individuals more susceptible to SARS-CoV-2. Telomere damage triggers DDR activation, leading to an upregulation of ACE2 and potentially increasing susceptibility to infection in the elderly.
Article
Oncology
Giulio Donati, Micol Rava, Marco Filipuzzi, Paola Nicoli, Laura Cassina, Alessandro Verrecchia, Mirko Doni, Simona Rodighiero, Federica Parodi, Alessandra Boletta, Christopher P. Vellano, Joseph R. Marszalek, Giulio F. Draetta, Bruno Amati
Summary: MYC activity is closely correlated with gene expression signatures related to oxidative phosphorylation in DLBCL, sensitizing B cells to the ETC complex I inhibitor IACS-010759. The combination of BCL2 inhibitor venetoclax and IACS-010759 showed synergy in DHL with concurrent activation of MYC and BCL2, while in BCL2-negative lymphoma cells, the Mcl-1 inhibitor S63845 potentiated killing by IACS-010759. This suggests a novel therapeutic approach against aggressive, MYC-associated DLBCL variants.
MOLECULAR ONCOLOGY
(2022)
Review
Cell Biology
Francesca Rossiello, Diana Jurk, Joao F. Passos, Fabrizio D'Adda di Fagagna
Summary: The article reviews the impact of telomere shortening and dysfunction on aging and a variety of age-related diseases in humans. Accumulation of senescent cells in aging organisms is believed to contribute to bodily dysfunction. Telomere shortening and damage are known causes of cellular senescence and aging. The authors argue that telomeric dysfunction plays a broad role in human pathologies associated with normal aging.
NATURE CELL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Dan Chen, Judit Z. Gervai, Adam Poti, Eszter Nemeth, Zoltan Szeltner, Bernadett Szikriszt, Zsolt Gyure, Judit Zamborszky, Marta Ceccon, Fabrizio d'Adda di Fagagna, Zoltan Szallasi, Andrea L. Richardson, David Szuts
Summary: Defects in BRCA1, BRCA2, and other genes involved in DNA repair have been found to increase the rate of mutagenesis. This study reveals that Y family translesion synthesis (TLS) polymerases play a role in the generation of spontaneous mutations in BRCA1 deficient cells. Furthermore, the protein 53BP1 regulates TLS and template switching in replicative DNA damage bypass.
NATURE COMMUNICATIONS
(2022)
Review
Oncology
Chiara Caprioli, Iman Nazari, Sara Milovanovic, Pier Giuseppe Pelicci
Summary: Single-cell technologies offer valuable insights into the development and therapeutic resistance mechanisms of myeloid neoplasms, enabling the development of more efficient immunotherapies.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biology
Nina Tanaskovic, Mattia Dalsass, Marco Filipuzzi, Giorgia Ceccotti, Alessandro Verrecchia, Paola Nicoli, Mirko Doni, Daniela Olivero, Diego Pasini, Haruhiko Koseki, Arianna Sabo, Andrea Bisso, Bruno Amati
Summary: Loss of Mga and PRC1.6 has no significant impact on Myc-induced lymphomagenesis in transgenic mice, but loss of Pcgf6 accelerates tumor formation. This suggests an unexpected tumor suppressor activity of Pcgf6 independent of Mga and PRC1.6.
LIFE SCIENCE ALLIANCE
(2022)
Article
Biochemistry & Molecular Biology
Chiara Priami, Daniela Montariello, Giulia De Michele, Federica Ruscitto, Andrea Polazzi, Simona Ronzoni, Giovanni Bertalot, Giorgio Binelli, Valentina Gambino, Lucilla Luzi, Marina Mapelli, Marco Giorgio, Enrica Migliaccio, Pier Giuseppe Pelicci
Summary: Aging is characterized by a decline in tissue regenerative capacity and resident stem cell function. This study reveals that p66Shc plays a crucial role in mammary gland aging by inducing p53/p44 signaling, leading to decreased symmetric divisions, reduced proliferation and regenerative potential of mammary stem cells.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Oncology
Elisabetta Todisco, Federica Gigli, Chiara Ronchini, Viviana Amato, Simona Sammassimo, Rocco Pastano, Gabriella Parma, Maria Teresa Lapresa, Francesco Bertolini, Chiara Corsini, Giuliana Gregato, Claudia Poletti, Pier Giuseppe Pelicci, Myriam Alcalay, Nicoletta Colombo, Corrado Tarella
Summary: In this study, it was found that EOC patients undergoing chemotherapy and prolonged PARPi therapy are at risk of developing therapy-related myeloid neoplasms (t-MNs), with poor outcomes and high mortality rates. Careful diagnostic procedures are strongly recommended for patients experiencing unusual cytopenias during PARPi therapy.
INTERNATIONAL JOURNAL OF CANCER
(2022)
Review
Biochemistry & Molecular Biology
Federica Ruscitto, Niccolo Roda, Chiara Priami, Enrica Migliaccio, Pier Giuseppe Pelicci
Summary: This review examines the classification, epidemiology, and impact of metastatic disease on prognosis and survival in breast cancer. The authors discuss the genetic and phenotypic heterogeneity of breast tumors, as well as the mechanisms underlying adaptive stress responses during metastatic progression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Correction
Oncology
Chiara Caprioli, Iman Nazari, Sara Milovanovic, Pier Giuseppe Pelicci
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
G. Tini, D. Trapani, B. A. Duso, P. Beria, G. Curigliano, P. G. Pelicci, L. Mazzarella
Summary: This study developed a distance-based accessibility index to assess the accessibility of clinical trials and analyzed the inequalities across countries and regions. The study found that the accessibility of clinical trials is unevenly distributed, especially in high-income and upper-middle-income countries. Although the accessibility increased over time, it did not keep pace with the increase in the number of trials.
Article
Biophysics
Elena Cerutti, Morgana D'Amico, Isotta Cainero, Pier Giuseppe Pelicci, Mario Faretta, Gaetano Ivan Dellino, Alberto Diaspro, Luca Lanzano
Summary: The molecular mechanisms of oncogene-induced genomic damage are still poorly understood. This study combines superresolution microscopy with image cross correlation spectroscopy to quantify alterations induced by the PML-RARa oncogene in an in vitro model of acute promyelocytic leukemia. The results demonstrate that activation of the oncogene leads to an increase in the fraction of transcription sites colocalized with PML/PML-RARa, resulting from the disruption of physiological PML bodies and the occurrence of PML-RARa microspeckles. The study also reveals a heterogeneous response of cells to the activation of the oncogene.
BIOPHYSICAL JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Laura Furia, Simone Pelicci, Mirco Scanarini, Pier Giuseppe Pelicci, Mario Faretta
Summary: 53BP1 protein plays an important role in sustaining the activity of the p53-regulated transcriptional program. This study uses an automated-microscopy protocol to analyze the evolution of the DNA-Damage Response (DDR) and demonstrates the movement of 53BP1 protein from damaged sites to the nucleoplasm, where it interacts with p53 and enhances the transcriptional regulation of the guardian of the genome protein.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Medicine, Research & Experimental
Giulio Donati, Paola Nicoli, Alessandro Verrecchia, Veronica Vallelonga, Ottavio Croci, Simona Rodighiero, Matteo Audano, Laura Cassina, Aya Ghsein, Giorgio Binelli, Alessandra Boletta, Nico Mitro, Bruno Amati
Summary: MYC is a key driver in multiple tumor types and can be targeted by drugs that suppress mitochondrial respiration. In this study, the mechanistic basis for the lethal interaction between MYC and respiratory complex I inhibitor IACS-010759 was unraveled. It was found that high-dose ascorbate synergized with IACS-010759 to kill MYC-overexpressing cells and improved therapeutic outcomes in B-cell lymphoma xenografts.
EMBO MOLECULAR MEDICINE
(2023)
Article
Biology
Alberto Magi, Gianluca Mattei, Alessandra Mingrino, Chiara Caprioli, Chiara Ronchini, GianMaria Frige, Roberto Semeraro, Davide Bolognini, Alessandro Rambaldi, Anna Candoni, Emanuela Colombo, Luca Mazzarella, Pier Giuseppe Pelicci
Summary: DNA methylation patterns in sparse CpG regions drive chemoresistance in Acute Myeloid Leukemia patients.
COMMUNICATIONS BIOLOGY
(2023)