Review
Health Care Sciences & Services
Sharon A. McGrath-Morrow, Cynthia C. Rothblum-Oviatt, Jennifer Wright, Haley Schlechter, Maureen A. Lefton-Greif, Valerie A. Natale, Thomas O. Crawford, Howard M. Lederman
Summary: Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive ataxia, oculocutaneous telangiectasias, and immune system impairment. Patients with A-T have an increased risk of malignancy, leading to premature death.
JOURNAL OF MULTIDISCIPLINARY HEALTHCARE
(2021)
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.
Review
Pharmacology & Pharmacy
Bhanu Priya, Srimadhavi Ravi, Sivapriya Kirubakaran
Summary: The DNA Damage and Response (DDR) pathway is crucial for maintaining genome integrity and preventing cancer development. The DDR pathway, particularly the ATM and ATR kinases, plays a vital role in recognizing and repairing DNA double-strand breaks (DSBs), a severe DNA damage that can lead to genomic instability. Cancer cells, with a high burden of DSBs, heavily rely on efficient DSB repair mechanisms for their survival. Therefore, targeting DSB repair pathways, such as ATM and ATR, can enhance the efficacy of DNA-damaging agents in cancer treatment. This review focuses on the roles of ATM and ATR in the DDR pathway, challenges in targeting these kinases, and current clinical trials of their inhibitors.
DRUG DISCOVERY TODAY
(2023)
Article
Biochemistry & Molecular Biology
Divya A. Shiroor, Kuang-Tse Wang, Bhargav D. Sanketi, Justin K. Tapper, Carolyn E. Adler
Summary: Stem cells acquire mutations during division, but can activate the DNA damage response network to repair or induce apoptosis. In planarian flatworms, ATM promotes radiation-induced apoptosis, which is important for long-term animal survival.
Article
Biochemistry & Molecular Biology
Sayanthooran Saravanabavan, Gopala K. Rangan
Summary: Increased DNA damage response signaling in kidney cyst-lining epithelial cells (CECs) may be a target for therapy in ADPKD. However, inhibiting ATM kinase and low-dose cisplatin together does not selectively induce cell death in CECs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Jakub Czarny, Marta Andrzejewska, Olga Zajac-Spychala, Elzbieta Latos-Grazynska, Agata Pastorczak, Kamila Wypyszczak, Aleksandra Szczawinska-Poplonyk, Izabela Niewiadomska-Wojnalowicz, Agnieszka Wziatek, Patrycja Marciniak-Stepak, Michal Dopierala, Jadwiga Maldyk, Katarzyna Jonczyk-Potoczna, Katarzyna Derwich
Summary: Ataxia-telangiectasia (AT) is a rare genetic disorder characterized by DNA repair defect, chromosomal instability, and hypersensitivity to radiation. Successful clinical management of patients with AT is challenging due to poor treatment response, high toxicity, and the need to avoid radiation exposure. This case report describes a 7-year-old female patient with AT and LBCL with IRF4 rearrangement who achieved a favorable outcome through treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Minsuk Kwon, Gahyun Kim, Ryul Kim, Kyu-Tae Kim, Seung Tae Kim, Simon Smith, Peter G. S. Mortimer, Jung Yong Hong, Arsene-Bienvenu Loembe, Itziar Irurzun-Arana, Loumpiana Koulai, Kyoung-Mee Kim, Won Ki Kang, Emma Dean, Woong-Yang Park, Jeeyun Lee
Summary: The combination of Ceralasertib and durvalumab has shown promising clinical activity and tolerability in patients with advanced gastric cancer (AGC). Certain patients showed better clinical responses, which were associated with loss of ATM expression and homologous repair deficiency.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2022)
Article
Oncology
Renata Neves, Blanca De Dios Perez, Rafal Panek, Sumit Jagani, Sophie Wilne, Jayesh M. Bhatt, Caterina Caputi, Emilia Cirillo, David J. Coman, Gregor Dueckers, Donald L. Gilbert, Mary Kay Koenig, Lobna Mansour, Elizabeth McDermott, Micaela Pauni, Claudio Pignata, Susan L. Perlman, Oscar Porras, Mariela Betina Porto, Katherine Schon, Pere Soler-Palacin, Sam Nick Russo, Masatoshi Takagi, Marc Tischkowitz, Claire Wainwright, Madhumita Dandapani, Cristine Glazebrook, Mohnish Suri, William P. Whitehouse, Robert A. Dineen
Summary: This study used the e-Delphi technique to investigate the current international practice and consensus regarding cancer surveillance in ataxia telangiectasia (A-T) patients. The survey revealed significant variations in cancer surveillance practices among experts and centers. Consensus was reached that evidence-based guidelines are needed for cancer surveillance in A-T patients, with specific recommendations for tests, age range, and surveillance intervals. However, further research is required in some areas.
Review
Biochemistry & Molecular Biology
Jacquelyne Ka-Li Sun, Genper Chi-Ngai Wong, Kim Hei-Man Chow
Summary: Cerebellar ataxia, a symptom of ataxia-telangiectasia (A-T), is the irreversible consequence of selective degeneration of cerebellar Purkinje neurons. A-T is caused by loss-of-function mutations in the ATM gene, which regulates DNA damage response and central carbon metabolic network. The review aims to explore the unexpected connections between these two cellular functions and their impact on the specific vulnerability of Purkinje neurons.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Oncology
Susan G. R. McDuff, Jennifer R. Bellon, Kristen M. Shannon, Michele A. Gadd, Samantha Dunn, Barry S. Rosenstein, Alice Y. Ho
Summary: Most breast cancer patients with ATM variants can safely receive adjuvant radiation therapy. Exceptions may include patients with specific rare variants, who should be cautious of an increased risk for developing contralateral breast cancer and minimize the contralateral breast dose.
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
(2021)
Article
Immunology
Kerstin Felgentreff, Catharina Schuetz, Ulrich Baumann, Christian Klemann, Dorothee Viemann, Simona Ursu, Eva-Maria Jacobsen, Klaus-Michael Debatin, Ansgar Schulz, Manfred Hoenig, Klaus Schwarz
Summary: DNA damage occurs constantly in cells due to internal and external factors, triggering different responses in lymphocyte subsets depending on maturation levels. These differences in DNA damage response play a role in cell survival and could be important for diagnostic purposes.
FRONTIERS IN IMMUNOLOGY
(2021)
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
Biology
Mark C. Johnson, Geylani Can, Miguel Monteiro Santos, Diana Alexander, Philip Zegerman
Summary: This study reveals that Rad53 phosphorylates the same substrates throughout the cell cycle, not just in S-phase, suggesting its roles beyond S-phase. By inhibiting 51d3 and Dbf4, Rad53 limits re-replication in G2/M, preventing gene amplification, and inhibiting these substrates in G1 prevents premature initiation at the G1/S transition. This redefinition of the 'S-phase checkpoint' has implications for understanding checkpoint function in cancers without proper cell cycle controls.
Article
Multidisciplinary Sciences
Heathcliff Dorado Garcia, Fabian Pusch, Yi Bei, Jennifer von Stebut, Glorymar Ibanez, Kristina Guillan, Koshi Imami, Dennis Guergen, Jana Rolff, Konstantin Helmsauer, Stephanie Meyer-Liesener, Natalie Timme, Victor Bardinet, Rocio Chamorro Gonzalez, Ian C. MacArthur, Celine Y. Chen, Joachim Schulz, Antje M. Wengner, Christian Furth, Birgit Lala, Angelika Eggert, Georg Seifert, Patrick Hundsoerfer, Marieluise Kirchner, Philipp Mertins, Matthias Selbach, Andrej Lissat, Frank Dubois, David Horst, Johannes H. Schulte, Simone Spuler, Daoqi You, Filemon Dela Cruz, Andrew L. Kung, Kerstin Haase, Michela DiVirgilio, Monika Scheer, Michael V. Ortiz, Anton G. Henssen
Summary: This study demonstrates that PAX3-FOXO1-expressing alveolar rhabdomyosarcoma (ARMS) cells are sensitive to ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Inhibition of ATR leads to replication stress exacerbation and reduced DNA repair pathway activity, increasing the sensitivity of ARMS cells to PARP1 inhibition. Treatment with ATR and PARP1 inhibitors in combination induces complete regression of primary patient-derived ARMS xenografts, suggesting potential clinical applications. Additionally, the study identifies the RAS-MAPK pathway and FOS gene family as inducers of resistance to ATR inhibition in ARMS cells.
NATURE COMMUNICATIONS
(2022)
Article
Genetics & Heredity
Sara Biagiotti, Ambra Barone, Mattia Paolo Aliano, Giulia Federici, Marco Malatesta, Caterina Caputi, Silvia Soddu, Vincenzo Leuzzi, Luciana Chessa, Mauro Magnani
Summary: Most ATM variants associated with Ataxia Telangiectasia are classified as variants with uncertain significance. This study focused on a specific ATM variant found in Lebanese brothers, revealing it to be pathogenic even though it causes an atypical phenotype. Dexamethasone showed therapeutic potential on this and possibly other missense ATM variants.
FRONTIERS IN GENETICS
(2021)
