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Beier F.,Telomere and Telomerase Group | Beier F.,RWTH Aachen | Martinez P.,Telomere and Telomerase Group | Blasco M.A.,Telomere and Telomerase Group
Journal of Hepatology | Year: 2015

Background & Aims: Large liver cell changes (LLCC) are characterized by pleomorphic large nuclei frequently found in liver diseases as chronic viral hepatitis and liver cirrhosis. The origin of this lesion remains cryptic, but the presence of LLCC is correlated with an increased risk of hepatocellular carcinoma. Telomeric repeat binding factor 1 (TRF1) is part of the shelterin complex and is essential for telomere protection. Ablation of TRF1 induces telomere fragility and fusions and chromosomal instability. Methods: In this study, we addressed the role of TRF1 in liver regeneration generating a mouse model with conditional deletion of TRF1 in the liver. Results: TRF1 deletion has no deleterious effects in liver and leads to increased ploidy of hepatocytes after 2/3 hepatectomy. Mice lacking TRF1 in the liver can survive for over one year without any evidence for altered liver function. Importantly, applying chronic replicative stress by frequent carbon tetrachloride (CCl4) injections, TRF1 deleted mice undergo ploidy changes consistent with endoreduplication and develop LLCC like lesions in the liver positive for p21, Cyclin D1 and PCNA as observed in humans. Conclusion: In summary, we provide mechanistic insight into the role of TRF1 in liver regeneration and provide a mouse model recapitulating the clinical features of LLCC. © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Source

Hummel S.,RWTH Aachen | Ferreira M.S.V.,RWTH Aachen | Heudobler D.,Internal Medicine III | Huber E.,University of Regensburg | And 10 more authors.
Blood | Year: 2015

Acute intestinal graft-versus-host disease (aGVHD) refractory to immunosuppressive treatment is a serious complication after allogenic hematopoietic stem cell transplantation (HSCT). The underlying mechanisms of refractory aGVHD of the gut are not fully understood. Although telomere length (TL) reflects the replicative history of a cell, critically short telomeres have been associated with replicative exhaustion and tissue failure. In this study, wedemonstrate that enterocytes of patients with refractory intestinal aGVHD show significantly increased proliferation, which translates into significant and critical telomere attrition following HSCT as compared with unaffected patients undergoing HSCT. Calculated telomere loss ina GVHD patients is 190bp/wk, therebymassively exceeding physiological steady-state TL shortening rates such as in lymphocytes (~50 bp/y). Our data support the hypothesis that increased compensatory proliferation following continued tissue damage can result in massive telomere loss in enterocytes of aGVHD patients. The present study introduces aGVHD-triggered increased cellular turnover and telomere loss with subsequent replicative exhaustion as a mechanism for refractory gut GVHD that is compatible with the long-term clinical aspect of the disease and provides a basis for stem cell protective therapies in the treatment of aGVHD. © 2015 by The American Society of Hematology. Source

Benitez-Buelga C.,Human Genetics Group | Vaclova T.,Human Genetics Group | Ferreira S.,Human Genetics Group | Urioste M.,Familial Cancer Clinical Unit | And 9 more authors.
Oncotarget | Year: 2016

We have recently shown that rs2304277 variant in the OGG1 glycosidase gene of the Base Excision Repair pathway can increase ovarian cancer risk in BRCA1 mutation carriers. In the present study, we aimed to explore the role of this genetic variant on different genome instability hallmarks to explain its association with cancer risk. We have evaluated the effect of this polymorphism on OGG1 transcriptional regulation and its contribution to telomere shortening and DNA damage accumulation. For that, we have used a series of 89 BRCA1 and BRCA2 mutation carriers, 74 BRCAX cases, 60 non-carrier controls and 23 lymphoblastoid cell lines (LCL) derived from BRCA1 mutation carriers and non-carriers. We have identified that this SNP is associated to a significant OGG1 transcriptional down regulation independently of the BRCA mutational status and that the variant may exert a synergistic effect together with BRCA1 or BRCA2 mutations on DNA damage and telomere shortening. These results suggest that this variant, could be associated to a higher cancer risk in BRCA1 mutation carriers, due to an OGG1 transcriptional down regulation and its effect on genome instability. Source

News Article | August 18, 2016
Site: http://www.biosciencetechnology.com/rss-feeds/all/rss.xml/all

Despite their especially compact structure that is difficult to access, telomeres transcribe information like the rest of the DNA. The RNAs resulting from this process are called TERRA and their function is essential in preserving these protective structures. This is the conclusion of a new study by the Telomere and Telomerase Group at the Spanish National Cancer Research Centre (CNIO), which has also located the part of the human genome where these molecules are "manufactured". This finding is consistent with the observations made two years ago by the same group, lead by Maria A. Blasco. On that occasion, they were working on mouse cells and they observed that the TERRA that protect the 20 chromosomes of this mammal originated exclusively in pair 18 and, to a lesser extent, in number 9. In the case of humans, the results now published in Nature Communications indicate that these RNAs are transcribed exclusively at one point. The researchers analysed 18 RNAs previously proposed as possible TERRA but only those arising from the long arm of chromosome 20 (20q) and at the short arm of chromosome X (Xp) showed TERRA features. To demonstrate that the RNAs transcribed at these two points were, indeed, TERRA, the authors genetically removed both loci using the CRISPR-CAS9 technology. They then noted that while the suppression of Xp had no significant consequences, the suppression of 20q had extremely negative effects on telomeres. "Identification of 20q as one of the major locus for human TERRA generation allows us to address the role of TERRA telomere biology," write the authors. After removing it in various cellular lines, they saw that there was a significant increase in DNA and telomere damage, as well as an increase in chromosome instability. This is the first time that the crucial role of TERRA in the preservation of telomeres has been demonstrated in any organism. "These results are striking because they clearly demonstrate that TERRA play an essential role in cell viability as well as in preserving telomeres; they are just as important to the functioning of telomeres as telomerase or shelterins, the proteins that protect the telomeres," explains Blasco. The discovery of the 20q region as the source of TERRA and the confirmation of the key role played by these RNAs in preserving telomeres opens the door to the study of certain syndromes in which alterations in this chromosomal region have been detected. Also, it offers a new path in the study of patients with telomeric disorders in which, however, no alterations in the genes normally involved -telomerase, shelterins- have been found.

Beier F.,Telomere and Telomerase Group | Beier F.,RWTH Aachen | Masouleh B.K.,RWTH Aachen | Buesche G.,Hannover Medical School | And 17 more authors.
Leukemia Research | Year: 2015

Myelodysplastic syndrome (MDS) associated with an acquired, isolated deletion of chromosome 5q (del (5q) MDS), represent a clonal disorder of hematopoiesis and a clinically distinct entity of MDS. Treatment of del (5q) MDS with the drug lenalidomide has significantly improved quality of life leading to transfusion independence and complete cytogenetic response rates (CCR) in the majority of patients. Telomeres are located at the end of eukaryotic chromosomes and are linked to replicative history/potential as well as genetic (in) stability of hematopoietic stem cells. Here, we analyzed telomere length (TL) dynamics before and under lenalidomide treatment in the peripheral blood and/or bone marrow of del (5q) patients enrolled in the LEMON-5 study (NCT01081431).Hematopoietic cells from del (5q) MDS patients were characterized by significantly shortened TL compared to age-matched healthy controls. Telomere loss was more accelerated in patients with longer disease duration (>2 years) and more pronounced cytopenias. Sequential analysis under lenalidomide treatment revealed that previously shortened TL in peripheral blood cells was significantly "elongated" towards normal levels within the first six months suggesting a shift from clonal del (5q) cells towards normal hematopoiesis in lenalidomide treated MDS patients.Taken together our findings suggest that the development of the del (5q) clone is associated with accelerated telomere shortening at diagnosis. However, upon induction of CCR and reoccurrence of normal hematopoiesis, the lack of a persistent TL deficit argues against telomere-mediated genetic instability neither as a disease-promoting event of del (5q) MDS nor for lenalidomide mediated development of secondary primary malignancies of the hematopoietic system in responding patients. © 2015 Elsevier Ltd. Source

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