Maria A Blasco

..Here, we focus on the current methods to assess cellular senescence, discriminating the advantages and disadvantages of several senescence biomarkers...

..These findings have inspired a number of potential therapeutic strategies that are based on telomerase and telomeres...

..Here, I will discuss how these different mouse models have contributed to our understanding on the role of telomeres and telomerase in cancer and aging...

..These links between epigenetic status and telomere-length regulation provide important new avenues for understanding processes such as cancer development and ageing, which are characterized by telomere-length defects...

..Here, we will discuss recent findings suggesting that telomeric chromatin shares many features with pericentric chromatin, and that disruption of telomeric heterochromatin results in changes in telomere length...

..This review focuses on the analysis of different mouse models for proteins that are important for telomere function, which have highlighted the importance of telomeres and telomerase for cancer and aging...

..Here, we will review the current evidence linking telomere shortening to aging and stem cell dysfunction...

..These results suggest a critical role of DNA-PKcs in both cancer and aging...

..In conclusion, these data link the dual role of DNA-PKcs in DNA repair and telomere length maintenance to organismal ageing and cancer...

..These results support the notion that absence of telomerase and short telomeres in combination with DNA repair deficiencies accelerate the aging process without impacting on tumorigenesis...

..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...

..Together, these results demonstrate that TRF1, like TRF2, negatively regulates telomere length in vivo by controlling the action of the XPF nuclease at telomeres; in addition, TRF1 has a unique role in the mitotic spindle checkpoint...

....

..Additionally, telomerase reintroduction into these mice results in a normal life span by preventing degenerative pathologies in the absence of increased tumorigenesis...

..Together, these results highlight the importance of telomere biology for iPS cell generation and functionality...

..These findings link SIRT1 to telomere biology and global DNA repair and provide new mechanistic explanations for the known functions of SIRT1 in protection from DNA damage and some age-associated pathologies...

..These findings place a telomere protein at the interface between telomere function and transcriptional regulation...

..These results are of particular relevance given that TRF2 is up-regulated in some human cancers. Furthermore, these data suggest that telomerase inhibition might not be effective to cease the growth of TRF2-overexpressing tumors...

..These results demonstrate the importance of chromatin architecture in the maintenance of telomere length homeostasis and reveal a novel role for histone lysine methylation in controlling telomere recombination...

..These results demonstrate that constitutive expression of Tert provides antiaging activity in the context of a mammalian organism...

..These findings indicate that telomerase overexpression extends the maximum lifespan of mice...

..These observations highlight the importance of telomere repeats in the establishment of constitutive heterochromatin at mammalian telomeres and subtelomeres and point to histone modifications as important in counting telomere repeats...

..These results highlight a role for MSH2 in the organismal response to dysfunctional telomeres, which in turn may be important in the pathobiology of human cancers bearing mutations in the MMR pathway...

....

..These results reveal a previously unnoticed role for mammalian ATR in telomere protection and stability...

..Telomere shortening in K5TRF2 mice is also accompanied by decreased abundance of telomeric transcripts. Together, these findings indicate a previously unnoticed role for TRF2 in the assembly of telomeric chromatin...

..Our results indicate that TelRNAs are novel components of mammalian telomeres, which are anticipated to be fundamental for understanding telomere biology and telomere-related diseases, such as cancer and ageing...

..These results highlight an unprecedented role for MMR in mediating the cellular response to dysfunctional telomeres in vivo by attenuating p21 induction...

..These observations indicate that the RB1 family is involved in maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin, linking tumour suppression and the epigenetic definition of chromatin...

....

..These results identify a pathway by which miR-290 directly regulates Rbl2-dependent Dnmt expression, indirectly affecting telomere-length homeostasis...

....

..These findings suggest that telomerase-based therapies could be useful prophylactic agents in FA aplastic anemia by preserving their telomere reserve in the context of the disease...

....

....

....

..Finally, we show that a number of human skin tumors have increased expression of TRF2, further highlighting a role for TRF2 in skin cancer...

..During the last years it has become evident that telomeres and telomerase are main components of the stem cell "ignition" mechanism, providing a way to restrain cancer and delay aging...

....

..The effects of telomeres and telomerase on stem cell biology anticipate their role in cancer and aging...

..Together, these results demonstrate a previously unappreciated role for DNA methylation in maintaining telomere integrity...

..These findings highlight Terc as a target for telomerase-based anticancer therapies...

..Taken together, these results highlight telomerase as a mediator of Myc-induced papillomatosis and suggest telomerase as a putative therapeutic target for Myc-dependent lesions...

..Together, these results represent proof of principle that mutations in TRF1 lead to the main clinical features of BMF...

..In intact mice, combined 53BP1/TRF1 deficiency in stratified epithelia resulted in earlier onset of DNA damage and increased CHK1 phosphorylation during embryonic development, leading to aggravation of skin phenotypes...

..These murine models are helping us to understand the consequences of telomere dysfunction for cancer, aging and DNA repair, as well as, the molecular mechanisms by which telomeres exert their protective function...

....

....

..K5-TRF2 mice represent a new tool to understand the consequences of critical telomere shortening a telomerase-proficient genetic background, more closely resembling human cancer and aging pathologies...

....

..Together, our results prove that cancer resistance can be enhanced by a simple genetic modification and in the absence of undesirable effects...

..All together, we conclude that the silencing of Ink4/Arf locus is rate-limiting for reprogramming, and its transient inhibition may significantly improve the generation of iPS cells...

....

..Both immune system defects are landmarks of immunosenescence. The study of the telomerase-deficient mouse model supports the notion that telomere shortening with age contributes to immunological dysfunction in the elderly...

..Finally, TA-65 dietary supplementation in female mice leads to an improvement of certain health-span indicators including glucose tolerance, osteoporosis and skin fitness, without significantly increasing global cancer incidence...

..We propose a novel mechanism for aneuploidy generation that involves impaired telomere replication upon loss of cohesin-SA1, with clear implications in tumourigenesis...

..Finally, the study of mice doubly deficient for Rad54 and DNA-PKcs showed that telomere fusions due to DNA-PKcs deficiency were not rescued in the absence of Rad54, suggesting that they are not mediated by Rad54 activity...

..More recently, the role of telomerase and telomere length in stem cells is starting to be elucidated...

..Finally, G5 Terc(-/-) hypersensitivity to MNU supports the notion that short telomeres interfere with proper DNA damage repair...

..These findings demonstrate that short telomeres have a direct impact on longevity in mammals, and they highlight the importance of performing longitudinal telomere studies to predict longevity...

..These findings demonstrate a connection between the Rb1 family and the control of telomere length in mammalian cells...

..We will also discuss the links between epigenetic alterations at mammalian telomeres and telomere-associated diseases...

..This Review discusses the role of telomeric proteins in cancer and ageing through modulating telomere length and protection, as well as regulating gene expression by binding to non-telomeric sites...

..Understanding the links between the epigenetic status of telomeres, TERRA/TelRNA and telomere homeostasis will open new avenues for our understanding of organismal development, cancer and ageing...

....

..These results suggest, as already shown in yeast, that most telomere chromatin is dispensable for proper attachment of mammalian meiotic chromosome ends to the nuclear envelope...

..Here, I will discuss these studies, as well as their implications for putative therapies based of telomerase inhibition of telomerase re-introduction for cancer or age-related diseases, respectively...

..These findings also revealed that the structure of telomeric chromatin is dynamic and controlled by epigenetic programmes, which are reversed by reprogramming...

..These mouse models have allowed the relevance of telomeres and telomerase in tumour development and the aging of the organism to be directly tested...

..We show here that this technique provides the accuracy and sensitivity to uncover associations between telomere length and human disease...

..Altogether, these results demonstrate that constitutive high levels of telomerase activity result in a decreased life span associated with an increased incidence of neoplasias as the organism ages...

..We propose that slight differences in the epigenetic configuration might account for the cell-to-cell variation in the strength of the DDR observed when groups of cells are challenged with DNA breaks...

..The overall balance between these convergent and divergent mechanisms guarantees fitness and a cancer-free life until late adulthood for most individuals...

..Together these mechanisms limit excessive or aberrant cellular proliferation, and so the state of senescence protects against the development of cancer. Recent evidence suggests that cellular senescence also may be involved in aging...

..The positive effects of telomerase on aging seem to come of the price of tumour promotion. These antagonistic roles of telomerase in aging and cancer may have important implications for putative telomerase based therapies...

..These recent developments indicate that our understanding of telomere biology remains incomplete and implicate additional complexity in the relationships among telomeres, telomerase and cancer...

..Here, we describe the different methodologies recently developed for telomere length quantification, as well as their potential applications for human aging studies...

..Telomere shortening has been related to vascular dysfunction and hypertension. In the present study, we analyzed the influence of telomerase deficiency and telomere shortening on arterial pressure (AP)...