Article
Multidisciplinary Sciences
Baocheng Liu, Yao He, Yaqiang Wang, He Song, Z. Hong Zhou, Juli Feigon
Summary: This study reveals the structure of human telomerase and its interaction with TPP1. The binding of TPP1 to TERT activates telomerase activity. Additionally, the study found that elements in TERT and TER involved in template and telomeric DNA handling are structurally similar to those in Tetrahymena telomerase, providing unique insights into the mechanism of telomerase activity.
Article
Biochemistry & Molecular Biology
Taylor Takasugi, Peili Gu, Fengshan Liang, Isabelle Staco, Sandy Chang
Summary: Malignant cancers activate telomere maintenance mechanisms through POT1, and loss of POT1 function promotes telomere elongation. Serial transplantation of Pot1b(-/-) sarcomas reveals shortened telomeres in early-generation and hyper-elongated telomeres recognized as damaged DNA in late-generation Pot1b(-/-) cells. RPA-ATR-dependent DNA damage response at telomeres recruits telomerase for hyper-elongation, while POT1b unfolds G-quadruplex and represses the DNA damage response.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Huan Wang, Tengfei Ma, Xiaotong Zhang, Wei Chen, Yina Lan, Guotao Kuang, Shih-Jui Hsu, Zibin He, Yuxi Chen, Jason Stewart, Anukana Bhattacharjee, Zhenhua Luo, Carolyn Price, Xuyang Feng
Summary: CTC1-TPP1 interaction plays a key role in telomerase termination by modulating CST binding to ssDNA and the ability of CST to recruit or engage partner proteins. OB-B domain is a key determinant of telomerase termination but not C-strand synthesis. CTC1-Delta B mutation greatly reduced CST-TPP1 interaction and weakened TPP1 association, leading to an inability to limit telomerase action.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Bruno Silva, Rajika Arora, Silvia Bione, Claus M. Azzalin
Summary: TERRA transcription actively destabilizes telomere integrity in ALT cells, thereby triggering BIR and promoting telomere elongation.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Valeria Savoca, Julieta Rivosecchi, Alice Gaiatto, Annalisa Rossi, Riccardo Mosca, Irene Gialdini, Lorena Zubovic, Toma Tebaldi, Paolo Macchi, Emilio Cusanelli
Summary: This study reveals that the stability of TERRA transcripts is regulated by the RNA-binding protein associated with lethal yellow mutation (RALY). Depletion of RALY leads to decreased levels of TERRA, impaired localization of TERRA at telomeres, and ultimately telomere damage. Furthermore, TERRA interacts with the poly(A)-binding protein nuclear 1 (PABPN1), suggesting an interplay between RALY and PABPN1 in regulating TERRA stability.
Article
Biochemistry & Molecular Biology
Patrick Lambert-Lanteigne, Adrian Young, Chantal Autexier
Summary: In human cancer cells, cellular immortalization relies on the maintenance of telomere length by telomerase. The interaction between telomere protein TPP1 and the telomerase reverse transcriptase (hTERT)'s N-terminal domain, TEN, regulates telomerase recruitment to telomeres. The hTERT 'insertion in fingers domain' (IFD) is involved in this process. The IFD domain can interact with TPP1, but its presence is not essential for the interaction. Several conserved residues in the IFD-TRAP region regulate telomerase recruitment and cell immortalization, and mutations in these residues compromise the interaction between the IFD domain and TPP1.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Genetics & Heredity
Fang Wang, Isaac J. Chamani, Danxia Luo, Kasey Chan, Paula Andrea Navarro, David L. Keefe
Summary: Inhibition of LINE-1 in mouse 2-cell embryos leads to significant downregulation of Dux, Zscan4, and LINE-1, as well as blocked telomere elongation. ZSCAN4 foci and their co-localization with telomeres are also significantly decreased, indicating the essential role of ZSCAN4 in telomere reprogramming during the 2-cell stage in mice.
JOURNAL OF ASSISTED REPRODUCTION AND GENETICS
(2021)
Article
Multidisciplinary Sciences
Ross A. Cordiner, Yuhui Dou, Rune Thomsen, Andrii Bugai, Sander Granneman, Torben Heick Jensen
Summary: Dynamic RNA-protein interactions play a crucial role in the co-transcriptional packaging of RNA polymerase II-derived transcripts. The authors employed temporal-iCLIP to investigate these interactions during the early phases of transcription and beyond, providing valuable insights into the temporal dynamics and functional roles of RNA-protein interactions.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Rita Valador Fernandes, Joachim Lingner
Summary: The study reveals the role of THOC in telomeric homeostasis through the co- and post-transcriptional regulation of TERRA R-loops. THOC counteracts the association of TERRA with telomeres by interfering with the formation of R-loops. THOC also promotes telomere stability by suppressing telomeric sister-chromatid exchange and C-circle accumulation in ALT cancer cells.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Cell Biology
Christian Hernandez-Guzman, Helios Gallego-Gutierrez, Bibiana Chavez-Munguia, Dolores Martin-Tapia, Lorenza Gonzalez-Mariscal
Summary: The study found that in ZO-2 knockdown cells, nuclear shape is abnormal and linked to an increase in DNA double strand breaks, but the cells do not undergo senescence. Lack of extracellular calcium can also cause irregular nuclear shape.
Article
Biochemistry & Molecular Biology
Mitchell A. Ellison, Sanchirmaa Namjilsuren, Margaret K. Shirra, Matthew S. Blacksmith, Rachel A. Schusteff, Eleanor M. Kerr, Fei Fang, Yufei Xiang, Yi Shi, Karen M. Arndt
Summary: The Paf1 complex is a transcription elongation factor that regulates transcription efficiency and impacts RNA synthesis. The subunits Cdc73 and Rtf1 of Paf1C are important for the association with RNA polymerase II on active genes.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Rajaraman Gopalakrishnan, Fred Winston
Summary: The histone chaperone Spt6 plays an important role in promoting elongation of RNAPII, maintaining chromatin structure, regulating histone modifications, and controlling mRNA processing. Through interactions with RNAPII and other factors, Spt6 is crucial for regulating the composition and function of the transcription elongation complex.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Cell Biology
Catherine L. W. Miller, Fred Winston
Summary: Spt6 is an important histone chaperone that regulates chromatin accessibility and plays a role in DNA replication and genome stability. Depletion or mutation of Spt6 impairs DNA replication and makes the cells sensitive to DNA replication stress. This impairment is independent of its association with RNAPII, suggesting that Spt6 mutants have a transcription-independent defect in DNA replication.
Article
Reproductive Biology
Sarah Potgieter, Christopher Eddy, Aditi Badrinath, Lauren Chukrallah, Toby Lo, Gayatri Mohanty, Pablo E. Visconti, Elizabeth M. Snyder
Summary: ADAD1 is a RNA-binding protein expressed in post-meiotic spermatids, playing a crucial role in the translation of mRNAs important for post-meiotic differentiation and nuclear and intracellular transport. Loss of ADAD1 leads to defective sperm and male infertility, with morphological and functional abnormalities. ADAD1 is involved in translational activation of target transcripts and regulation of protein transport, including delayed protein accumulation and impaired subcellular localization. These defects are associated with disrupted manchette and LINC complex, and reduced ribosome association and abnormal localization of nuclear pore complex proteins. Together, ADAD1's impact on nuclear transport affects the proper functioning of the LINC complex and the manchette, leading to the observed physiological defects in the Adad1 phenotype.
BIOLOGY OF REPRODUCTION
(2023)
Article
Genetics & Heredity
Raul Sanchez-Vazquez, Paula Martinez, Maria A. Blasco
Summary: This study demonstrates how extracellular signals can regulate telomere protection and length through modifications in TRF1 protein. Mutations in TRF1 lead to decreased telomere binding, increased DNA damage, accelerated telomere shortening, impaired response to proliferative signals, and decreased tumorigenesis potential. It highlights the role of PI3K/AKT pathway in regulating telomere maintenance and suggests potential targets for cancer therapy.
Article
Cell Biology
Sergio Pineiro-Hermida, Paula Martinez, Maria A. Blasco
Summary: The study suggests that short or dysfunctional telomeres play a protective role in murine asthma by reducing airway hyperresponsiveness and mucus secretion following exposure to allergens.
Article
Geriatrics & Gerontology
Maria Giulia Bacalini, Anna Reale, Marco Malavolta, Fabio Ciccarone, Maria Moreno-Villanueva, Martijn E. T. Dolle, Eugene Jansen, Tilman Grune, Efstathios S. Gonos, Christiane Schoen, Juergen Bernhardt, Beatrix Grubeck-Loebenstein, Ewa Sikora, Olivier Toussaint, Florence Debacq-Chainiaux, Miriam Capri, Antti Hervonen, Mikko Hurme, P. Eline Slagboom, Nicolle Breusing, Valentina Aversano, Stefano Tagliatesta, Claudio Franceschi, Maria A. Blasco, Alexander Buerkle, Paola Caiafa, Michele Zampieri
Summary: The study found that changes in subtelomeric DNA methylation correlate with ageing progression, with linear changes observed in the general population, slower changes in the offspring of centenarians, and accelerated changes in Down syndrome individuals. These findings suggest that subtelomeric DNA methylation changes are a typical sign of ageing. Additionally, the effects of age on subtelomeric DNA methylation are mostly independent of other variables evaluated, including demographics and dietary/health habits.
Article
Oncology
Maria Monteagudo, Paula Martinez, Luis J. Leandro-Garcia, Angel M. Martinez-Montes, Bruna Calsina, Marta Pulgarin-Alfaro, Alberto Diaz-Talavera, Sara Mellid, Rocio Leton, Eduardo Gil, Manuel Perez-Martinez, Diego Megias, Raul Torres-Ruiz, Sandra Rodriguez-Perales, Patricia Gonzalez, Eduardo Caleiras, Scherezade Jimenez-Villa, Giovanna Roncador, Cristina Alvarez-Escola, Rita M. Regojo, Maria Calatayud, Sonsoles Guadalix, Maria Curras-Freixes, Elena Rapizzi, Letizia Canu, Svenja Noelting, Hanna Remde, Martin Fassnacht, Nicole Bechmann, Graeme Eisenhofer, Massimo Mannelli, Felix Beuschlein, Marcus Quinkler, Cristina Rodriguez-Antona, Alberto Cascon, Maria A. Blasco, Cristina Montero-Conde, Mercedes Robledo
Summary: Recent studies have highlighted the importance of telomere maintenance mechanisms involving TERT and ATRX genes in metastatic pheochromocytoma and paraganglioma (mPPGL). In addition to validating the predictive value of TERT and ATRX in mPPGL progression, this study also identified NOP10 as a novel prognostic risk marker of mPPGLs. By analyzing 29 telomere-related genes, it was found that NOP10 plays a role in telomerase-dependent telomere length maintenance in these tumors, suggesting its potential as a new marker for identifying metastatic-risk patients. The proposal to implement NOP10 immunohistochemistry (IHC) as part of the current marker panel for PPGL patients aims to improve clinical diagnoses.
Editorial Material
Chemistry, Physical
Paula Martinez, Maria A. Blasco
Summary: Telomerase, discovered over 35 years ago by Elizabeth H. Blackburn and Carol W. Greider, is now seen as a promising approach to curing some age-related diseases and cancer. However, it took time for telomerase to be recognized and become in the spotlight.
Article
Cell Biology
Giuseppe Bosso, Pablo Lanuza-Gracia, Sergio Pineiro-Hermida, Merve Yilmaz, Rosa Serrano, Maria A. Blasco
Summary: BRAF(V600E) mutation is common in cancer and its expression leads to DNA damage response, inflammation, and differential changes in cell cycle and senescence-associated proteins in lung epithelia.
CELL DEATH & DISEASE
(2022)
Review
Biochemistry & Molecular Biology
Miriam Ayora, David Fraguas, Renzo Abregu-Crespo, Sandra Recio, Maria A. Blasco, Ana Moises, Aksinya Derevyanko, Celso Arango, Covadonga M. Diaz-Caneja
Summary: The meta-analysis found that leukocyte telomere length was significantly shorter in patients with schizophrenia and related disorders compared to healthy controls, with no significant effects of age or illness duration on this difference. The results support the hypothesis of accelerated cellular aging in schizophrenia and related disorders, highlighting the need for large longitudinal studies with repeated telomere length measurements and appropriate assessments of associated factors.
MOLECULAR PSYCHIATRY
(2022)
Article
Genetics & Heredity
Paula Martinez, Raul Sanchez-Vazquez, Iole Ferrara-Romeo, Rosa Serrano, Juana M. Flores, Maria A. Blasco
Summary: By generating a mouse model for the human POT1(R117C) mutation, this study found that the mutation leads to longer telomeres and exerts dominant-negative effects at telomeres. Heterozygous mice with this mutation also develop angiosarcomas, including cardiac angiosarcomas. This research provides important insights into human cancers initiated by POT1 mutations.
Article
Multidisciplinary Sciences
Sergio Pineiro-Hermida, Paula Martinez, Giuseppe Bosso, Juana Maria Flores, Sarita Saraswati, Jane Connor, Raphael Lemaire, Maria A. Blasco
Summary: Depletion of TRF1 does not lead to interstitial lung fibrosis, highlighting the relevance of alveolar type II cells in this disease.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Jorge Sanz-Ros, Nekane Romero-Garcia, Cristina Mas-Bargues, Daniel Monleon, Juozas Gordevicius, Robert T. Brooke, Mar Dromant, Ana Diaz, Aksinya Derevyanko, Ana Guio-Carrion, Aurora Roman-Dominguez, Marta Ingles, Maria A. Blasco, Steve Horvath, Jose Vina, Consuelo Borras
Summary: This study found that treatment of old animals with ADSC-sEVs derived from young animals can improve various parameters associated with aging and reduce frailty. This treatment induces proregenerative effects and reduces oxidative stress, inflammation, and senescence in muscle and kidney. Additionally, tissue epigenetic age decreases and metabolome shifts to a youth-like pattern after this treatment.
Article
Oncology
Cristina Montero-Conde, Luis Javier Leandro-Garcia, Angel M. Martinez-Montes, Paula Martinez, Francisco J. Moya, Rocio Leton, Eduardo Gil, Natalia Martinez-Puente, Sonsoles Guadalix, Maria Curras-Freixes, Laura Garcia-Tobar, Carles Zafon, Mireia Jorda, Garcilaso Riesco-Eizaguirre, Patricia Gonzalez-Garcia, Maria Monteagudo, Rafael Torres-Perez, Veronika Mancikova, Sergio Ruiz-Llorente, Manuel Perez-Martinez, Guillermo Pita, Juan Carlos Galofre, Anna Gonzalez-Neira, Alberto Cascon, Cristina Rodriguez-Antona, Diego Megias, Maria A. Blasco, Eduardo Caleiras, Sandra Rodriguez-Perales, Mercedes Robledo
Summary: Comprehensive molecular studies were conducted on thyroid tumors to identify prognostic biomarkers. Telomere-related alterations, especially TERT and TERC, were found in aggressive tumors. Short telomeres led to reorganization in the 5p subtelomeric region, resulting in increased gene upregulation and a more relaxed chromatin configuration in the tumors.
CLINICAL AND TRANSLATIONAL MEDICINE
(2022)
Review
Biochemistry & Molecular Biology
Carlos Lopez-Otin, Maria A. Blasco, Linda Partridge, Manuel Serrano, Guido Kroemer
Summary: Aging is driven by hallmarks that manifest with age, accelerate aging when accentuated experimentally, and can be decelerated, stopped, or reversed with therapeutic interventions. The twelve proposed hallmarks of aging include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected with each other and with the recently proposed hallmarks of health.
Article
Biochemistry & Molecular Biology
Sergio Pineiro-Hermida, Giuseppe Bosso, Raul Sanchez-Vazquez, Paula Martinez, Maria A. Blasco
Summary: Non-small cell lung cancer (NSCLC) is a leading cause of cancer death, and tumor progression is influenced by the interaction between cancer cells and the tumor microenvironment. Increased copy number and mRNA expression of TERT, a catalytic subunit of telomerase, is associated with decreased survival in NSCLC patients. Targeting telomeres may be an effective therapeutic approach in NSCLC treatment.
CELL DEATH AND DIFFERENTIATION
(2023)
Article
Cell Biology
Paula Martinez, Raul Sanchez-Vazquez, Arpita Saha, Maria S. Rodriguez-Duque, Sara Naranjo-Gonzalo, Joy S. Osorio-Chavez, Ana V. Villar-Ramos, Maria A. Blasco
Summary: The severity of COVID-19 increases with age, suggesting that organismal aging contributes to its fatality. Previous studies have shown that COVID-19 severity is correlated with shorter telomeres in patient's leukocytes. Lung injury is a prominent feature of acute SARS-CoV-2 infection, which can progress to lung fibrosis. In this study, we found that post-COVID-19 patients have shorter telomeres and increased lung fibrosis compared to age-matched controls with lung cancer, suggesting a link between short telomeres in ATII cells and long-term lung fibrosis in post-COVID-19 patients.
Article
Cell Biology
Sarita Saraswati, Paula Martinez, Osvaldo Grana-Castro, Maria A. Blasco
Summary: Accumulation of short telomeres is a hallmark of aging and can sensitize kidneys to develop fibrosis by influencing the EMT program. Deletion of Trf1 in kidneys also leads to fibrosis and EMT activation. This study shows that short and dysfunctional telomeres enhance the genetic program associated with epithelial-to-mesenchymal transition in two mouse models of kidney fibrosis.