Publications by authors named "Maria Thanasoula"

17 Publications

  • Page 1 of 1

Metabolic profiling of organic and fatty acids in chronic and autoimmune diseases.

Adv Clin Chem 2021 15;101:169-229. Epub 2020 Jul 15.

Metabolomic Medicine Clinic, Athens, Greece; European Institute of Nutritional Medicine, E.I.Nu.M, Rome, Italy. Electronic address:

Metabolomics is a powerful tool of omics that permits the simultaneous identification of metabolic perturbations in several autoimmune and chronic diseases. Several parameters can affect a metabolic profile, from the population characteristics to the selection of the analytical method. In the current chapter, we summarize the main analytical methods and results of the metabolic profiling of fatty and organic acids performed in human metabolomic studies for asthma, COPD, psoriasis and Hashimoto's thyroiditis. We discuss the most significant metabolic alterations associated with these diseases, after comparison of either a single patient's group with healthy controls or several patient's subgroups of different disease severity and phenotype with healthy controls or of a patient's group before and after treatment. Finally, we present critical metabolic patterns that are associated with each disease and their potency for the unraveling of disease pathogenesis, prediction, diagnosis, patient stratification and treatment selection.
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http://dx.doi.org/10.1016/bs.acc.2020.06.003DOI Listing
July 2021

Telomerase and telomeres in aging theory and chronographic aging theory (Review).

Mol Med Rep 2020 Sep 25;22(3):1679-1694. Epub 2020 Jun 25.

Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece.

The current review focuses on the connection of telomerase and telomeres with aging. In this review, we describe the changes in telomerase and telomere length (TEL) during development, their role in carcinogenesis processes, and the consequences of reduced telomerase activity. More specifically, the connection of TEL in peripheral blood cells with the development of aging‑associated diseases is discussed. The review provides systematic data on the role of telomerase in mitochondria, the biology of telomeres in stem cells, as well as the consequences of the forced expression of telomerase (telomerization) in human cells. Additionally, it presents the effects of chronic stress exposure on telomerase activity, the effect of TEL on fertility, and the effect of nutraceutical supplements on TEL. Finally, a comparative review of the chronographic theory of aging, presented by Olovnikov is provided based on currently available scientific research on telomere, telomerase activity, and the nature of aging by multicellular organisms.
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http://dx.doi.org/10.3892/mmr.2020.11274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411297PMC
September 2020

Analysis of the intricate effects of polyunsaturated fatty acids and polyphenols on inflammatory pathways in health and disease.

Food Chem Toxicol 2020 Sep 5;143:111558. Epub 2020 Jul 5.

Laboratory of Toxicology and Forensic Sciences, Medical School, University of Crete, 71003, Heraklion, Greece; Department of Analytical and Forensic Medical Toxicology, Sechenov University, 2-4 Bolshaya Pirogovskaya st, 119991, Moscow, Russia. Electronic address:

Prevention and treatment of non-communicable diseases (NCDs), including cardiovascular disease, diabetes, obesity, cancer, Alzheimer's and Parkinson's disease, arthritis, non-alcoholic fatty liver disease and various infectious diseases; lately most notably COVID-19 have been in the front line of research worldwide. Although targeting different organs, these pathologies have common biochemical impairments - redox disparity and, prominently, dysregulation of the inflammatory pathways. Research data have shown that diet components like polyphenols, poly-unsaturated fatty acids (PUFAs), fibres as well as lifestyle (fasting, physical exercise) are important factors influencing signalling pathways with a significant potential to improve metabolic homeostasis and immune cells' functions. In the present manuscript we have reviewed scientific data from recent publications regarding the beneficial cellular and molecular effects induced by dietary plant products, mainly polyphenolic compounds and PUFAs, and summarize the clinical outcomes expected from these types of interventions, in a search for effective long-term approaches to improve the immune system response.
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http://dx.doi.org/10.1016/j.fct.2020.111558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335494PMC
September 2020

Chronic Inflammation in the Context of Everyday Life: Dietary Changes as Mitigating Factors.

Int J Environ Res Public Health 2020 06 10;17(11). Epub 2020 Jun 10.

Department Forensic Sciences and Toxicology, University of Crete, Faculty of Medicine, 71003 Heraklion, Greece.

The lifestyle adopted by most people in Western societies has an important impact on the propensity to metabolic disorders (e.g., diabetes, cancer, cardiovascular disease, neurodegenerative diseases). This is often accompanied by chronic low-grade inflammation, driven by the activation of various molecular pathways such as STAT3 (signal transducer and activator of transcription 3), IKK (IκB kinase), MMP9 (matrix metallopeptidase 9), MAPK (mitogen-activated protein kinases), COX2 (cyclooxigenase 2), and NF-Kβ (nuclear factor kappa-light-chain-enhancer of activated B cells). Multiple intervention studies have demonstrated that lifestyle changes can lead to reduced inflammation and improved health. This can be linked to the concept of real-life risk simulation, since humans are continuously exposed to dietary factors in small doses and complex combinations (e.g., polyphenols, fibers, polyunsaturated fatty acids, etc.). Inflammation biomarkers improve in patients who consume a certain amount of fiber per day; some even losing weight. Fasting in combination with calorie restriction modulates molecular mechanisms such as m-TOR, FOXO, NRF2, AMPK, and sirtuins, ultimately leads to significantly reduced inflammatory marker levels, as well as improved metabolic markers. Moving toward healthier dietary habits at the individual level and in publicly-funded institutions, such as schools or hospitals, could help improving public health, reducing healthcare costs and improving community resilience to epidemics (such as COVID-19), which predominantly affects individuals with metabolic diseases.
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http://dx.doi.org/10.3390/ijerph17114135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312944PMC
June 2020

Telomere length and telomerase activity in osteoporosis and osteoarthritis.

Exp Ther Med 2020 Mar 24;19(3):1626-1632. Epub 2019 Dec 24.

Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece.

Osteoarthritis (OA) and osteoporosis (OP) are associated skeletal pathologies and have as a distinct feature the abnormal reconstruction of the subchondral bone. OA and OP have been characterized as age-related diseases and have been associated with telomere shortening and altered telomerase activity (TA). This review discusses the role of telomeres and telomerase in OA and OP pathologies and focuses on the usability of telomere length (TL) and the rate of telomere shortening as potential disease biomarkers. A number of studies have demonstrated that telomere shortening may contribute to OA and OP as an epigenetic factor. Therefore, it has been claimed that the measurement of TL of chondrocytes and/or peripheral blood cells may be an appropriate marker for the evaluation of the progression of these diseases. However, there is a need to be perform further studies with larger cohorts, with the aim of obtaining objective results and a better understanding of the association between TL, inflammation and aging, in order to provide further insight into the pathophysiology of degenerative joint diseases.
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http://dx.doi.org/10.3892/etm.2019.8370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027092PMC
March 2020

Metabolic Fingerprint of Chronic Obstructive Lung Diseases: A New Diagnostic Perspective.

Metabolites 2019 Nov 26;9(12). Epub 2019 Nov 26.

Laboratory of Toxicology and Forensic Sciences, Medical School, University of Crete, 71003 Heraklion, Greece.

Chronic obstructive lung disease (COLD) is a group of airway diseases, previously known as emphysema and chronic bronchitis. The heterogeneity of COLD does not allow early diagnosis and leads to increased morbidity and mortality. The increasing number of COLD incidences stresses the need for precision medicine approaches that are specific to the patient. Metabolomics is an emerging technology that allows for the discrimination of metabolic changes in the cell as a result of environmental factors and specific genetic background. Thus, quantification of metabolites in human biofluids can provide insights into the metabolic state of the individual in real time and unravel the presence of, or predisposition to, a disease. In this article, the advantages of and potential barriers to putting metabolomics into clinical practice for COLD are discussed. Today, metabolomics is mostly lab-based, and research studies with novel COLD-specific biomarkers are continuously being published. Several obstacles in the research and the market field hamper the translation of these data into clinical practice. However, technological and computational advances will facilitate the clinical interpretation of data and provide healthcare professionals with the tools to prevent, diagnose, and treat COLD with precision in the coming decades.
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http://dx.doi.org/10.3390/metabo9120290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949962PMC
November 2019

Discovery of potent telomerase activators: Unfolding new therapeutic and anti-aging perspectives.

Mol Med Rep 2019 Oct 23;20(4):3701-3708. Epub 2019 Aug 23.

Department of Clinical Pharmacy, University of Medicine and Pharmacy, Faculty of Pharmacy, 200349 Craiova, Romania.

Telomere length, a marker of cellular aging, decreases with age and it has been associated with aging‑related diseases. Environmental factors, including diet and lifestyle factors, affect the rate of telomere shortening which can be reversed by telomerase. Telomerase activation by natural molecules has been suggested to be an anti‑aging modulator that can play a role in the treatment of aging‑related diseases. This study aimed to investigate the effect of natural compounds on telomerase activity in human peripheral blood mononuclear cells (PBMCs). The tested compounds included Centella asiatica extract formulation (08AGTLF), Astragalus extract formulation (Nutrient 4), TA‑65 (containing Astragalus membranaceus extract), oleanolic acid (OA), maslinic acid (MA), and 3 multi‑nutrient formulas (Nutrients 1, 2 and 3) at various concentrations. The mean absorbance values of telomerase activity measured following treatment with some of the above‑mentioned formulations were statistically significantly higher compared to those of the untreated cells. In particular, in order of importance with respect to telomerase activation from highest to lowest, 08AGTLF, OA, Nutrient 4, TA‑65, MA, Nutrient 3 and Nutrient 2, triggered statistically significant increase in telomerase activity compared to the untreated cells. 08AGTLF reached the highest levels of telomerase activity reported to date, at least to our knowledge, increasing telomerase activity by 8.8 folds compared to untreated cells, while Nutrient 4 and OA were also potent activators (4.3‑fold and 5.9‑fold increase, respectively). On the whole, this study indicates that the synergistic effect of nutrients and natural compounds can activate telomerase and produce more potent formulations. Human clinical studies using these formulations are required to evaluate their mode of action. This would reveal the health benefits of telomerase activation through natural molecules and would shed new light onto the treatment of aging‑related diseases.
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http://dx.doi.org/10.3892/mmr.2019.10614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755196PMC
October 2019

Basis of catalytic assembly of the mitotic checkpoint complex.

Nature 2017 02 19;542(7642):498-502. Epub 2017 Jan 19.

Department of Mechanistic Cell Biology, Max-Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.

In mitosis, for each daughter cell to inherit an accurate copy of the genome from the mother cell, sister chromatids in the mother cell must attach to microtubules emanating from opposite poles of the mitotic spindle, a process known as bi-orientation. A surveillance mechanism, termed the spindle assembly checkpoint (SAC), monitors the microtubule attachment process and can temporarily halt the separation of sister chromatids and the completion of mitosis until bi-orientation is complete. SAC failure results in abnormal chromosome numbers, termed aneuploidy, in the daughter cells, a hallmark of many tumours. The HORMA-domain-containing protein mitotic arrest deficient 2 (MAD2) is a subunit of the SAC effector mitotic checkpoint complex (MCC). Structural conversion from the open to the closed conformation of MAD2 is required for MAD2 to be incorporated into the MCC. In vitro, MAD2 conversion and MCC assembly take several hours, but in cells the SAC response is established in a few minutes. Here, to address this discrepancy, we reconstituted a near-complete SAC signalling system with purified components and monitored assembly of the MCC in real time. A marked acceleration in MAD2 conversion and MCC assembly was observed when monopolar spindle 1 (MPS1) kinase phosphorylated the MAD1-MAD2 complex, triggering it to act as the template for MAD2 conversion and therefore contributing to the establishment of a physical platform for MCC assembly. Thus, catalytic activation of the SAC depends on regulated protein-protein interactions that accelerate the spontaneous but rate-limiting conversion of MAD2 required for MCC assembly.
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http://dx.doi.org/10.1038/nature21384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448665PMC
February 2017

ATM/ATR checkpoint activation downregulates CDC25C to prevent mitotic entry with uncapped telomeres.

EMBO J 2012 Aug 27;31(16):3398-410. Epub 2012 Jul 27.

Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, UK.

Shelterin component TRF2 prevents ATM activation, while POT1 represses ATR signalling at telomeres. Here, we investigate the mechanism of G2/M arrest triggered by telomeres uncapped through TRF2 or POT1 inhibition in human cells. We find that telomere damage-activated ATR and ATM phosphorylate p53, as well as CHK1 and CHK2, thus activating two independent pathways to prevent progression into mitosis with uncapped telomeres. Surprisingly, telomere damage targets the CDC25C phosphatase for proteasome degradation in G2/M. CHK1/CHK2-dependent phosphorylation of CDC25C at Ser 216 is required for CDC25C nuclear export and destruction, which in turn acts to sustain the G2/M arrest elicited by TRF2- or POT1-depleted telomeres. In addition, CDC25C is transcriptionally downregulated by p53 in response to telomere damage. These mechanisms are distinct from the canonical DNA damage response to ionizing radiation, which triggers cell-cycle arrest through CDC25A destruction. Thus, dysfunctional telomeres promote ATM/ATR-dependent degradation of CDC25C phosphatase to block mitotic entry, thereby preventing telomere dysfunction-driven genomic instability.
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http://dx.doi.org/10.1038/emboj.2012.191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419928PMC
August 2012

BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping.

Nat Struct Mol Biol 2010 Dec 14;17(12):1461-9. Epub 2010 Nov 14.

Telomere and Genome Stability Group, The Cancer Research UK/Medical Research Council Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK.

The tumor suppressor protein BRCA2 is a key component of the homologous recombination pathway of DNA repair, acting as the loader of RAD51 recombinase at sites of double-strand breaks. Here we show that BRCA2 associates with telomeres during the S and G2 phases of the cell cycle and facilitates the loading of RAD51 onto telomeres. Conditional deletion of Brca2 and inhibition of Rad51 in mouse embryonic fibroblasts (MEFs), but not inactivation of Brca1, led to shortening of telomeres and accumulation of fragmented telomeric signals--a hallmark of telomere fragility that is associated with replication defects. These findings suggest that BRCA2-mediated homologous recombination reactions contribute to the maintenance of telomere length by facilitating telomere replication and imply that BRCA2 has an essential role in maintaining telomere integrity during unchallenged cell proliferation. Mouse mammary tumors that lacked Brca2 accumulated telomere dysfunction-induced foci. Human breast tumors in which BRCA2 was mutated had shorter telomeres than those in which BRCA1 was mutated, suggesting that the genomic instability in BRCA2-deficient tumors was due in part to telomere dysfunction.
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http://dx.doi.org/10.1038/nsmb.1943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998174PMC
December 2010

Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites.

Nat Cell Biol 2010 Aug 11;12(8):768-80. Epub 2010 Jul 11.

Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, Madrid, E-28029, Spain.

Rap1 is a component of the shelterin complex at mammalian telomeres, but its in vivo role in telomere biology has remained largely unknown to date. Here we show that Rap1 deficiency is dispensable for telomere capping but leads to increased telomere recombination and fragility. We generated cells and mice deleted for Rap1; mice with Rap1 deletion in stratified epithelia were viable but had shorter telomeres and developed skin hyperpigmentation in adulthood. By performing chromatin immunoprecipitation coupled with ultrahigh-throughput sequencing, we found that Rap1 binds to both telomeres and to extratelomeric sites through the (TTAGGG)(2) consensus motif. Extratelomeric Rap1-binding sites were enriched at subtelomeric regions, in agreement with preferential deregulation of subtelomeric genes in Rap1-deficient cells. More than 70% of extratelomeric Rap1-binding sites were in the vicinity of genes, and 31% of the genes deregulated in Rap1-null cells contained Rap1-binding sites, suggesting a role for Rap1 in transcriptional control. These findings place a telomere protein at the interface between telomere function and transcriptional regulation.
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http://dx.doi.org/10.1038/ncb2081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792482PMC
August 2010

TPP1 is required for TERT recruitment, telomere elongation during nuclear reprogramming, and normal skin development in mice.

Dev Cell 2010 May;18(5):775-89

Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3, Madrid E-28029, Spain.

The TPP1/ACD protein (hereafter TPP1) is a component of the shelterin complex at mammalian telomeres. Here we find that Tpp1-deficient mouse embryonic fibroblasts (MEFs) show increased chromosomal instability including sister chromatid fusions and chromosomes with multitelomeric signals related to telomere fragility. Tpp1 deletion decreases both TERT (the telomerase catalytic subunit) binding to telomeres in MEFs and telomerase function at chromosome ends in vivo. Abrogation of Tpp1 abolished net telomere elongation in the context of nuclear reprogramming of MEFs into induced pluripotent stem cells, whereas Tpp1 deletion in stratified epithelia of Tpp1(Delta/Delta)K5-Cre mice resulted in perinatal death, severe skin hyperpigmentation, and impaired hair follicle morphogenesis. p53 deficiency rescues skin hyperpigmentation and hair growth in these mice, indicating that p53 restricts proliferation of Tpp1-deficient cells. These results suggest a telomere-capping model where TPP1 protects telomere integrity and regulates telomerase recruitment to telomeres, thereby preventing early occurrence of degenerative pathologies.
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http://dx.doi.org/10.1016/j.devcel.2010.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631760PMC
May 2010

53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers.

Nat Struct Mol Biol 2010 Jun 9;17(6):688-95. Epub 2010 May 9.

Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Germ-line mutations in breast cancer 1, early onset (BRCA1) result in predisposition to breast and ovarian cancer. BRCA1-mutated tumors show genomic instability, mainly as a consequence of impaired recombinatorial DNA repair. Here we identify p53-binding protein 1 (53BP1) as an essential factor for sustaining the growth arrest induced by Brca1 deletion. Depletion of 53BP1 abrogates the ATM-dependent checkpoint response and G2 cell-cycle arrest triggered by the accumulation of DNA breaks in Brca1-deleted cells. This effect of 53BP1 is specific to BRCA1 function, as 53BP1 depletion did not alleviate proliferation arrest or checkpoint responses in Brca2-deleted cells. Notably, loss of 53BP1 partially restores the homologous-recombination defect of Brca1-deleted cells and reverts their hypersensitivity to DNA-damaging agents. We find reduced 53BP1 expression in subsets of sporadic triple-negative and BRCA-associated breast cancers, indicating the potential clinical implications of our findings.
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http://dx.doi.org/10.1038/nsmb.1831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912507PMC
June 2010

p53 prevents entry into mitosis with uncapped telomeres.

Curr Biol 2010 Mar 11;20(6):521-6. Epub 2010 Mar 11.

Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Old Road Campus, Oxford OX37DQ, UK.

Telomeres are protected by capping structures consisting of core protein complexes that bind with sequence specificity to telomeric DNA. In their absence, telomeres trigger a DNA damage response, materialized in accumulation at the telomere of damage response proteins, e.g., phosphorylated histone H2AX (gammaH2AX), into telomere-dysfunction-induced foci. Telomere uncapping occurs transiently in every cell cycle in G2, following DNA replication, but little is known about how protective structures are reassembled or whether this process is controlled by the cell-cycle surveillance machinery. Here, we report that telomere capping is monitored at the G2/M transition by the p53/p21 damage response pathway. Unlike their wild-type counterparts, human and mouse cells lacking p53 or p21 progress into mitosis prematurely with persisting uncapped telomeres. Furthermore, artificially uncapped telomeres delay mitotic entry in a p53- and p21-dependent manner. Uncapped telomeres that persist in mitotic p53-deficient cells are shorter than average and religate to generate end-to-end fusions. These results suggest that a p53-dependent pathway monitors telomere capping after DNA replication and delays G2/M progression in the presence of unprotected telomeres. This mechanism maintains a cell-cycle stage conducive for capping reactions and prevents progression into stages during which uncapped telomeres are prone to deleterious end fusions.
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http://dx.doi.org/10.1016/j.cub.2010.01.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959573PMC
March 2010

Identification and in vitro characterization of follicle stimulating hormone (FSH) receptor variants associated with abnormal ovarian response to FSH.

J Clin Endocrinol Metab 2010 Feb 8;95(2):529-36. Epub 2010 Jan 8.

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, Room FMB 329J, New Haven, Connecticut 06520, USA.

Context: FSH mediates cyclic follicle growth and development and is widely used for controlled ovarian stimulation in women undergoing infertility treatment. The ovarian response of women to FSH is variable, ranging from poor response to ovarian hyperstimulation.

Objective: We investigated whether genetic alterations of the FSH receptor (FSHR) contribute to this variability.

Design And Patients: Our approach was to study women undergoing treatment with in vitro fertilization falling into the edges of the normal distribution of ovarian response to FSH, with respect to age.

Setting: We conducted the study at the Yale Fertility Clinic.

Methods: We extracted RNA from cumulus cells surrounding the oocytes of women undergoing in vitro fertilization and analyzed the FSHR mRNA by RT-PCR and sequencing.

Results: We identified four abnormal FSHR splicing products (three exon deletions and one intron insertion) in the FSHR mRNA in 37% (13 of 35) of women tested. All alterations affected the extracellular ligand-binding portion of the receptor without causing a frameshift. When transfected in HEK293T cells, all four splicing variants showed markedly decreased cAMP activation compared to controls. Untransfected cells showed no response to FSH, whereas all the cell lines showed normal cAMP activation when treated with forskolin, a nonreceptor-mediated cAMP stimulant. None of the normal or mutant forms showed any response to LH or TSH.

Conclusions: Our findings strongly indicate FSHR variants as being an intrinsic genetic cause of some forms of infertility and identify a need for functional characterization of these variants and the investigation of more individualized ovarian stimulation protocols.
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http://dx.doi.org/10.1210/jc.2009-1304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840851PMC
February 2010

Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice.

Genes Dev 2009 Sep 13;23(17):2060-75. Epub 2009 Aug 13.

Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid E-28029, Spain.

The telomere repeat-binding factor 1 (TERF1, referred to hereafter as TRF1) is a component of mammalian telomeres whose role in telomere biology and disease has remained elusive. Here, we report on cells and mice conditionally deleted for TRF1. TRF1-deleted mouse embryonic fibroblasts (MEFs) show rapid induction of senescence, which is concomitant with abundant telomeric gamma-H2AX foci and activation of the ATM/ATR downstream checkpoint kinases CHK1 and CHK2. DNA damage foci are rescued by both ATM and ATM/ATR inhibitors, further indicating that both signaling pathways are activated upon TRF1 deletion. Abrogation of the p53 and RB pathways bypasses senescence but leads to chromosomal instability including sister chromatid fusions, chromosome concatenation, and occurrence of multitelomeric signals (MTS). MTS are also elevated in ATR-deficient MEFs or upon treatment with aphidicolin, two conditions known to induce breakage at fragile sites, suggesting that TRF1-depleted telomeres are prone to breakage. To address the impact of these molecular defects in the organism, we deleted TRF1 in stratified epithelia of TRF1(Delta/Delta)K5-Cre mice. These mice die perinatally and show skin hyperpigmentation and epithelial dysplasia, which are associated with induction of telomere-instigated DNA damage, activation of the p53/p21 and p16 pathways, and cell cycle arrest in vivo. p53 deficiency rescues mouse survival but leads to development of squamous cell carcinomas, demonstrating that TRF1 suppresses tumorigenesis. Together, these results demonstrate that dysfunction of a telomere-binding protein is sufficient to produce severe telomeric damage in the absence of telomere shortening, resulting in premature tissue degeneration and development of neoplastic lesions.
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http://dx.doi.org/10.1101/gad.543509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751970PMC
September 2009

RAD51C facilitates checkpoint signaling by promoting CHK2 phosphorylation.

J Cell Biol 2009 May;185(4):587-600

Cancer Research UK/Medical Research Council Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford OX3 7DQ, England, UK.

The RAD51 paralogues act in the homologous recombination (HR) pathway of DNA repair. Human RAD51C (hRAD51C) participates in branch migration and Holliday junction resolution and thus is important for processing HR intermediates late in the DNA repair process. Evidence for early involvement of RAD51 during DNA repair also exists, but its function in this context is not understood. In this study, we demonstrate that RAD51C accumulates at DNA damage sites concomitantly with the RAD51 recombinase and is retained after RAD51 disassembly, which is consistent with both an early and a late function for RAD51C. RAD51C recruitment depends on ataxia telangiectasia mutated, NBS1, and replication protein A, indicating it functions after DNA end resection but before RAD51 assembly. Furthermore, we find that RAD51C is required for activation of the checkpoint kinase CHK2 and cell cycle arrest in response to DNA damage. This suggests that hRAD51C contributes to the protection of genome integrity by transducing DNA damage signals in addition to engaging the HR machinery.
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http://dx.doi.org/10.1083/jcb.200811079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711581PMC
May 2009
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