The role of recombination in telomere length maintenance

2009 ◽  
Vol 37 (3) ◽  
pp. 589-595 ◽  
Author(s):  
Nicola J. Royle ◽  
Aarón Méndez-Bermúdez ◽  
Athanasia Gravani ◽  
Clara Novo ◽  
Jenny Foxon ◽  
...  
Keyword(s):  
Cell Division ◽  
Telomere Length ◽  
Genome Instability ◽  
Nijmegen Breakage Syndrome ◽  
Dna Helicase ◽  
Telomere Maintenance ◽  
Alternative Lengthening ◽  
Pathway Activation

Human telomeres shorten during each cell division, predominantly because of incomplete DNA replication. This eventually results in short uncapped telomeres that elicit a DNA-damage response, leading to cellular senescence. However, evasion of senescence results in continued cell division and telomere erosion ultimately results in genome instability. In the long term, this genome instability is not sustainable, and cancer cells activate a TMM (telomere maintenance mechanism), either expression of telomerase or activation of the ALT (alternative lengthening of telomeres) pathway. Activation of the ALT mechanism results in deregulation of recombination-based activities at telomeres. Thus ALT+ cells show elevated T-SCE (telomere sister-chromatid exchange), misprocessing of t-loops that cap chromosomes and recombination-based processes between telomeres or between telomeres and ECTRs (extrachromosomal telomeric repeats). Some or all of these processes underlie the chaotic telomere length maintenance that allows cells in ALT+ tumours unlimited replicative capacity. ALT activation is also associated with destabilization of a minisatellite, MS32. The connection between the minisatellite instability and the deregulation of recombination-based activity at telomeres is not understood, but analysis of the minisatellite can be used as a marker for ALT. It is known that telomere length maintenance in ALT+ cells is dependent on the MRN [MRE11 (meiotic recombination 11)–Rad50–NBS1 (Nijmegen breakage syndrome 1)] complex, but knowledge of the role of other genes, including the Werner's (WRN) and Bloom's (BLM) syndrome DNA helicase genes, is still limited.

scholarly journals RAD50 and RAD51 Define Two Pathways That Collaborate to Maintain Telomeres in the Absence of Telomerase

Genetics ◽  
1999 ◽  
Vol 152 (1) ◽  
pp. 143-152 ◽  
Author(s):  
Siyuan Le ◽  
J Kent Moore ◽  
James E Haber ◽  
Carol W Greider
Keyword(s):  
Cell Death ◽  
Telomere Length ◽  
Gene Conversion ◽  
De Novo ◽  
Dna Recombination ◽  
Telomere Maintenance ◽  
Triple Mutant ◽  
Yeast Telomerase ◽  
Telomere Lengthening

Abstract Telomere length is maintained by the de novo addition of telomere repeats by telomerase, yet recombination can elongate telomeres in the absence of telomerase. When the yeast telomerase RNA component, TLC1, is deleted, telomeres shorten and most cells die. However, gene conversion mediated by the RAD52 pathway allows telomere lengthening in rare survivor cells. To further investigate the role of recombination in telomere maintenance, we assayed telomere length and the ability to generate survivors in several isogenic DNA recombination mutants, including rad50, rad51, rad52, rad54, rad57, xrs2, and mre11. The rad51, rad52, rad54, and rad57 mutations increased the rate of cell death in the absence of TLC1. In contrast, although the rad50, xrs2, and mre11 strains initially had short telomeres, double mutants with tlc1 did not affect the rate of cell death, and survivors were generated at later times than tlc1 alone. While none of the double mutants of recombination genes and tlc1 (except rad52 tlc1) blocked the ability to generate survivors, a rad50 rad51 tlc1 triple mutant did not allow the generation of survivors. Thus RAD50 and RAD51 define two separate pathways that collaborate to allow cells to survive in the absence of telomerase.

scholarly journals The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 949 ◽  
Author(s):  
Marta Recagni ◽  
Joanna Bidzinska ◽  
Nadia Zaffaroni ◽  
Marco Folini
Keyword(s):  
Cancer Cells ◽  
Tumor Biology ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Limited Information ◽  
Adaptive Responses ◽  
Therapeutic Implications ◽  
Telomerase Inhibitors ◽  
Alternative Lengthening

Telomere maintenance mechanisms (i.e., telomerase activity (TA) and the alternative lengthening of telomere (ALT) mechanism) contribute to tumorigenesis by providing unlimited proliferative capacity to cancer cells. Although the role of either telomere maintenance mechanisms seems to be equivalent in providing a limitless proliferative ability to tumor cells, the contribution of TA and ALT to the clinical outcome of patients may differ prominently. In addition, several strategies have been developed to interfere with TA in cancer, including Imetelstat that has been the first telomerase inhibitor tested in clinical trials. Conversely, the limited information available on the molecular underpinnings of ALT has hindered thus far the development of genuine ALT-targeting agents. Moreover, whether anti-telomerase therapies may be hampered or not by possible adaptive responses is still debatable. Nonetheless, it is plausible hypothesizing that treatment with telomerase inhibitors may exert selective pressure for the emergence of cancer cells that become resistant to treatment by activating the ALT mechanism. This notion, together with the evidence that both telomere maintenance mechanisms may coexist within the same tumor and may distinctly impinge on patients’ outcomes, suggests that ALT may exert an unexpected role in tumor biology that still needs to be fully elucidated.

scholarly journals Alternative Lengthening of Telomeres and Chromatin Status

Genes ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 45 ◽  
Author(s):  
Ion Udroiu ◽  
Antonella Sgura
Keyword(s):  
Homologous Recombination ◽  
Reverse Transcriptase ◽  
Spatial Heterogeneity ◽  
Telomere Length ◽  
Epigenetic Modifications ◽  
Alternative Lengthening Of Telomeres ◽  
Telomere Elongation ◽  
Alternative Lengthening ◽  
Alt Activity

Telomere length is maintained by either telomerase, a reverse transcriptase, or alternative lengthening of telomeres (ALT), a mechanism that utilizes homologous recombination (HR) proteins. Since access to DNA for HR enzymes is regulated by the chromatin status, it is expected that telomere elongation is linked to epigenetic modifications. The aim of this review is to elucidate the epigenetic features of ALT-positive cells. In order to do this, it is first necessary to understand the telomeric chromatin peculiarities. So far, the epigenetic nature of telomeres is still controversial: some authors describe them as heterochromatic, while for others, they are euchromatic. Similarly, ALT activity should be characterized by the loss (according to most researchers) or formation (as claimed by a minority) of heterochromatin in telomeres. Besides reviewing the main works in this field and the most recent findings, some hypotheses involving the role of telomere non-canonical sequences and the possible spatial heterogeneity of telomeres are given.

scholarly journals Nijmegen Breakage Syndrome (NBS) is a Telomeropathy: Analysis of Telomere Length in NBS Homo- and Heterozygotes and Humanized Nbs Mice

2019 ◽  
Author(s):  
Raneem Habib ◽  
Ryong Kim ◽  
Heidemarie Neitzel ◽  
Ilja Demuth ◽  
Krystyna Chrzanowska ◽  
...  
Keyword(s):  
Telomere Length ◽  
Cancer Incidence ◽  
Genetic Instability ◽  
Nijmegen Breakage Syndrome ◽  
Survival Times ◽  
Telomere Shortening ◽  
Cancer Rate ◽  
Telomere Attrition ◽  
After Cancer

AbstractThe autosomal recessive genetic disorder Nijmegen breakage syndrome (NBS) is characterized by a defect in DNA double-strand break repair protein nibrin and chromosome instability associated with a high predisposition to cancer. Here we hypothesized that impaired nibrin/MRE11/RAD50 telomere maintenance complex may also affect telomere length and modulate the cancer phenotype.Telomere length was studied in blood from 38 homozygous and 27 heterozygous individuals, in one homozygous fetus, and in sex NBS lymphoblastoid cell lines (all with the founder mutation c.657_661del5), and in three humanized Nbs mice, using qPCR, TRF and Q-FISH.Telomere lengths were markedly but uniformly reduced to 20-40% of healthy controls. There was no correlation between telomere length and severity of clinical phenotype or age of death. By contrast, individual patients with very short telomeres displayed long survival times after cancer manifestation. Mildly accelerated telomere attrition was found in older NBS heterozygotes. In the NBS-fetus, the spinal cord, brain and heart had the longest telomeres, skin the shortest. Humanized Nbs mice (with much longer telo-meres than those in human beings) did not show accelerated telomere attrition.Our data clearly show that NBS is a secondary telomeropathy with unique features. Te- lomere attrition in NBS may cause genetic instability and contribute to the high cancer incidence in NBS. On the other hand, short telomeres may prevent an even worse pheno-type when a tumor has developed. These data may help to understand the high cancer rate in NBS and also the bifunctional role of telomere shortening in cancerogenesis.Author SummaryDNA damage is harmful because it leads to mutations in genes that initiate or accelerate cancerogenesis. The devastating consequences of DNA damage are manifested in diseases with non-functional repair pathways such as Nijmegen breakage syndrome (NBS). A common feature of these diseases is a high tumor incidence. However, cancer incidence varies and is not clear why it is highest for NBS. In a previous study, we have shown that the underlying nebrin mutation not only leads to defective DNA repair but also to higher degree of oxidative stress that generates further DNA lesions. Nibrin may play also an important role in protecting chromosome ends, the telomeres, from inap-propriate DNA repair. Therefore we examined the telomere length in NBS and show markedly reduced values in affected patients but not in NBC mice (with much milder phenotype and longer telomeres). Telomere attrition contributes to genetic instability and may thus contribute to the high cancer incidence in NBS. Individual patients with very short telomeres, however, displayed long survival times after cancer manifestation. Thus, short telomeres may also prevent an even worse phenotype when a tumor has developed. These data are fundamental to understanding the high cancer rate in NBS and also the bifunctional role of telomere shortening in cancer.

scholarly journals Transcriptional activity of TRF2 is telomere length dependent

2016 ◽  
Author(s):  
Ananda Kishore Mukherjee ◽  
Shalu Sharma ◽  
Parashar Dhapola ◽  
Dhurjhoti Saha ◽  
Tabish Hussain ◽  
...  
Keyword(s):  
Telomere Length ◽  
Genome Stability ◽  
Telomere Maintenance ◽  
Regulatory Control ◽  
Gene Promoters ◽  
Multiple Gene ◽  
Telomere Repeat ◽  
Genome Wide ◽  
Binding Factor

AbstractTRF2 is a telomere repeat binding factor crucial for telomere maintenance and genome stability. An emerging non-conventional role of TRF2 is as a transcriptional regulator through extra-telomeric bindings. Herein we report that increase in telomere length leads to sequestration of TRF2 at the telomeres leading to reduced extra-telomeric TRF2 occupancy genome wide. Decrease in TRF2 occupancy was found on multiple gene promoters in cells with elongated telomeres, including the cell cycle regulator kinase-p21. We found that TRF2 is a transcriptional repressor of p21, and, interestingly, TRF2-mediated regulatory control of p21 is telomere length dependent.

scholarly journals SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling

2021 ◽  
Vol 14 (689) ◽  
pp. eabe9613
Author(s):  
Nathaniel J. Robinson ◽  
Masaru Miyagi ◽  
Jessica A. Scarborough ◽  
Jacob G. Scott ◽  
Derek J. Taylor ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Intracellular Signaling ◽  
Binding Protein ◽  
Telomere Maintenance ◽  
Nucleocytoplasmic Shuttling ◽  
Iκb Kinase ◽  
Alternative Lengthening ◽  
Telomere Binding Protein ◽  
Sumo Ligase

The maintenance of telomere length supports repetitive cell division and therefore plays a central role in cancer development and progression. Telomeres are extended by either the enzyme telomerase or the alternative lengthening of telomeres (ALT) pathway. Here, we found that the telomere-associated protein SLX4IP dictates telomere proteome composition by recruiting and activating the E3 SUMO ligase PIAS1 to the SLX4 complex. PIAS1 SUMOylated the telomere-binding protein RAP1, which disrupted its interaction with the telomere-binding protein TRF2 and facilitated its nucleocytoplasmic shuttling. In the cytosol, RAP1 bound to IκB kinase (IKK), resulting in activation of the transcription factor NF-κB and its induction of Jagged-1 expression, which promoted Notch signaling and the institution of ALT. This axis could be targeted therapeutically in ALT-driven cancers and in tumor cells that develop resistance to antitelomerase therapies. Our results illuminate the mechanisms underlying SLX4IP-dependent telomere plasticity and demonstrate the role of telomere proteins in directly coordinating intracellular signaling and telomere maintenance dynamics.

scholarly journals Telomeres and Cancer

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1405
Author(s):  
Hueng-Chuen Fan ◽  
Fung-Wei Chang ◽  
Jeng-Dau Tsai ◽  
Kao-Min Lin ◽  
Chuan-Mu Chen ◽  
...  
Keyword(s):  
Telomere Length ◽  
Molecular Mechanisms ◽  
Telomere Maintenance ◽  
Cancer Development ◽  
Telomere Elongation ◽  
Metabolism Pathway ◽  
Length Regulation ◽  
Telomere Length Regulation ◽  
Genome Protection

Telomeres cap the ends of eukaryotic chromosomes and are indispensable chromatin structures for genome protection and replication. Telomere length maintenance has been attributed to several functional modulators, including telomerase, the shelterin complex, and the CST complex, synergizing with DNA replication, repair, and the RNA metabolism pathway components. As dysfunctional telomere maintenance and telomerase activation are associated with several human diseases, including cancer, the molecular mechanisms behind telomere length regulation and protection need particular emphasis. Cancer cells exhibit telomerase activation, enabling replicative immortality. Telomerase reverse transcriptase (TERT) activation is involved in cancer development through diverse activities other than mediating telomere elongation. This review describes the telomere functions, the role of functional modulators, the implications in cancer development, and the future therapeutic opportunities.

Escherichia coli and Neisseria gonorrhoeae UvrD helicase unwinds G4 DNA structures

2017 ◽  
Vol 474 (21) ◽  
pp. 3579-3597 ◽  
Author(s):  
Kaustubh Shukla ◽  
Roshan Singh Thakur ◽  
Debayan Ganguli ◽  
Desirazu Narasimha Rao ◽  
Ganesh Nagaraju
Keyword(s):  
Escherichia Coli ◽  
Neisseria Gonorrhoeae ◽  
Genome Instability ◽  
Excision Repair ◽  
Telomere Maintenance ◽  
Dna Double Strand Breaks ◽  
E Coli ◽  
G4 Dna

G-quadruplex (G4) secondary structures have been implicated in various biological processes, including gene expression, DNA replication and telomere maintenance. However, unresolved G4 structures impede replication progression which can lead to the generation of DNA double-strand breaks and genome instability. Helicases have been shown to resolve G4 structures to facilitate faithful duplication of the genome. Escherichia coli UvrD (EcUvrD) helicase plays a crucial role in nucleotide excision repair, mismatch repair and in the regulation of homologous recombination. Here, we demonstrate a novel role of E. coli and Neisseria gonorrhoeae UvrD in resolving G4 tetraplexes. EcUvrD and N. gonorrhoeae UvrD were proficient in unwinding previously characterized tetramolecular G4 structures. Notably, EcUvrD was equally efficient in resolving tetramolecular and bimolecular G4 DNA that were derived from the potential G4-forming sequences from the genome of E. coli. Interestingly, in addition to resolving intermolecular G4 structures, EcUvrD was robust in unwinding intramolecular G4 structures. These data for the first time provide evidence for the role of UvrD in the resolution of G4 structures, which has implications for the in vivo role of UvrD helicase in G4 DNA resolution and genome maintenance.

Telomere dynamics in Fancg-deficient mouse and human cells

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 3927-3935 ◽  
Author(s):  
Sonia Franco ◽  
Henri J. van de Vrugt ◽  
Piedad Fernández ◽  
Miguel Aracil ◽  
Fre Arwert ◽  
...  
Keyword(s):  
Telomere Length ◽  
Bone Marrow Cells ◽  
Human Cells ◽  
Telomere Maintenance ◽  
Deficient Mouse ◽  
Early Passage ◽  
Telomere Shortening ◽  
Hematopoietic Stem ◽  
Telomere Dynamics

Abstract A number of DNA repair proteins also play roles in telomere metabolism. To investigate whether the accelerated telomere shortening reported in Fanconi anemia (FA) hematopoietic cells relates to a direct role of the FA pathway in telomere maintenance, we have analyzed telomere dynamics in Fancg-deficient mouse and human cells. We show here that both hematopoietic (stem and differentiated bone marrow cells, B and T lymphocytes) and nonhematopoietic (germ cells, mouse embryonic fibroblasts [MEFs]) Fancg-/- mouse cells display normal telomere length, normal telomerase activity, and normal chromosome end-capping, even in the presence of extensive clastogen-induced cytogenetic instability (mitomycin C [MMC], gamma-radiation). In addition, telomerase-deficient MEFs with humanlike telomere length and decreased Fancg expression (G5 Terc-/-/Fancg shRNA3 MEFs) display normal telomere maintenance. Finally, early-passage primary fibroblasts from patients with FA of complementation group G as well as primary human cells with reduced FANCG expression (FANCG shRNA IMR90 cells) show no signs of telomere dysfunction. Our observations indicate that accelerated telomere shortening in patients with FA is not due to a role of FANCG at telomeres but instead may be secondary to the disease. 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. (Blood. 2004;104:3927-3935)

scholarly journals Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity

2021 ◽  
Vol 12 ◽  
Author(s):  
Di-Xian Wang ◽  
Xu-Dong Zhu ◽  
Xiao-Ru Ma ◽  
Li-Bin Wang ◽  
Zhao-Jun Dong ◽  
...  
Keyword(s):  
Telomere Length ◽  
Cellular Senescence ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Nuclear Entry ◽  
Differentiation Factor ◽  
Culture Model ◽  
Key Enzyme

Maintenance of telomere length is essential to delay replicative cellular senescence. It is controversial on whether growth differentiation factor 11 (GDF11) can reverse cellular senescence, and this work aims to establish the causality between GDF11 and the telomere maintenance unequivocally. Using CRISPR/Cas9 technique and a long-term in vitro culture model of cellular senescence, we show here that in vitro genetic deletion of GDF11 causes shortening of telomere length, downregulation of telomeric reverse transcriptase (TERT) and telomeric RNA component (TERC), the key enzyme and the RNA component for extension of the telomere, and reduction of telomerase activity. In contrast, both recombinant and overexpressed GDF11 restore the transcription of TERT in GDF11KO cells to the wild-type level. Furthermore, loss of GDF11-induced telomere shortening is likely caused by enhancing the nuclear entry of SMAD2 which inhibits the transcription of TERT and TERC. Our results provide the first proof-of-cause-and-effect evidence that endogenous GDF11 plays a causal role for proliferative cells to maintain telomere length, paving the way for potential rejuvenation of the proliferative cells, tissues, and organs.

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