Telomerase Activity and Telomere Length in APL: May Be Proliferative and Prognostic Markers.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4236-4236 ◽  
Author(s):  
Seyed Hamidolah Ghaffari ◽  
Nilofar Shayan-Asl ◽  
Abdolhamid Jamialahmadi ◽  
Ardeshir Ghavamzadeh ◽  
Kamran Alimoghaddam
Keyword(s):  
Telomere Length ◽  
Prognostic Markers ◽  
Telomerase Activity ◽  
Size Difference ◽  
Activity Levels ◽  
Telomeric Dna ◽  
Pcr Assay ◽  
Peripheral Blood Mononuclear ◽  
Normal Individuals ◽  
Associated Proteins

Abstract Introduction: The telomeric DNA together with its associated proteins protects the chromosome ends from degradation or aberrant recombination. Telomerase and telomere are extensively investigated as potential diagnostic and prognostic markers in human tumors. In this study, we aim to investigate the significance of telomerase activity (TA) and telomere length (TL) in patients with acute promyelocytic leukemia (APL). Methods: About 300 sequential peripheral blood mononuclear cell (PBMC) samples were collected from 40 patients with APL (32 newly diagnosed and 8 relapsed), at diagnosis, during and after therapy with Arsenic Trioxide. TA was assessed by TRAP-ELISA and -PAGE procedures. Terminal restriction fragment (TRF) length was determined by Southern blot analysis, using a Chemiluminescence-based assay. Quantification of PML-RARα/G6PDH transcripts was carried out by real-time PCR assay. Results: About 90% of the APL patients had a significant reduction in TRF length (median 3.5, ranged 2.3 to 6.7 kbp) relative to the age-matched control or to that at the time of CR (median 11.37; ranged 8.90 to 14.70 kbp) from the same patients (P<0.0001). A significance positive correlation between telomere length and PML-RARα expression was found in the APL patients (P=0.001). In all the APL patients, telomerase activity was elevated in comparison with normal individuals (P<0.001). The telomerase activity levels were significantly higher in patients with short TRF. The group of patients with shortened TRF and elevated TA had a significantly poorer overall survival. The levels of TA were even significantly higher and the TL size difference of leukemic from non-leukemic was significantly longer in relapsed patients than patients with the primary APL. Conclusion: Short telomere and high telomerase levels in the APL patients are mainly a consequence of extensive proliferative histories and they correlate with the disease progression. The shortened telomere length and the elevated telomerase activity may serve as prognostic factors for a subset of APL patients with more aggressive disease and poor outcome, and who may not respond favourably to arsenic therapy.

Telomere Length in Peripheral Blood Mononuclear Cells of Patients on Chronic Hemodialysis Is Related With Telomerase Activity and Treatment Duration

2015 ◽  
Vol 39 (9) ◽  
pp. 756-764 ◽  
Author(s):  
Ioannis Stefanidis ◽  
Georgios Voliotis ◽  
Vassilios Papanikolaou ◽  
Ioanna Chronopoulou ◽  
Theodoros Eleftheriadis ◽  
...  
Keyword(s):  
Telomere Length ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Treatment Duration ◽  
Mononuclear Cells ◽  
Telomerase Activity ◽  
Chronic Hemodialysis ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

scholarly journals Yeast Est2p Affects Telomere Length by Influencing Association of Rap1p with Telomeric Chromatin

2008 ◽  
Vol 28 (7) ◽  
pp. 2380-2390 ◽  
Author(s):  
Hong Ji ◽  
Christopher J. Adkins ◽  
Bethany R. Cartwright ◽  
Katherine L. Friedman
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Telomere Length ◽  
Specific Binding ◽  
Telomerase Activity ◽  
Negative Regulator ◽  
Wild Type ◽  
Telomeric Dna ◽  
Telomere Length Homeostasis

ABSTRACT In Saccharomyces cerevisiae, the sequence-specific binding of the negative regulator Rap1p provides a mechanism to measure telomere length: as the telomere length increases, the binding of additional Rap1p inhibits telomerase activity in cis. We provide evidence that the association of Rap1p with telomeric DNA in vivo occurs in part by sequence-independent mechanisms. Specific mutations in EST2 (est2-LT) reduce the association of Rap1p with telomeric DNA in vivo. As a result, telomeres are abnormally long yet bind an amount of Rap1p equivalent to that observed at wild-type telomeres. This behavior contrasts with that of a second mutation in EST2 (est2-up34) that increases bound Rap1p as expected for a strain with long telomeres. Telomere sequences are subtly altered in est2-LT strains, but similar changes in est2-up34 telomeres suggest that sequence abnormalities are a consequence, not a cause, of overelongation. Indeed, est2-LT telomeres bind Rap1p indistinguishably from the wild type in vitro. Taken together, these results suggest that Est2p can directly or indirectly influence the binding of Rap1p to telomeric DNA, implicating telomerase in roles both upstream and downstream of Rap1p in telomere length homeostasis.

scholarly journals Functional Diversification of Replication Protein A Paralogs and Telomere Length Maintenance in Arabidopsis

Genetics ◽  
2020 ◽  
Vol 215 (4) ◽  
pp. 989-1002
Author(s):  
Behailu B. Aklilu ◽  
François Peurois ◽  
Carole Saintomé ◽  
Kevin M. Culligan ◽  
Daniela Kobbe ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Telomere Length ◽  
Protein A ◽  
Replication Protein A ◽  
Telomerase Activity ◽  
Replication Protein ◽  
Telomeric Dna ◽  
Telomere Shortening ◽  
Replication Group

Replication protein A (RPA) is essential for many facets of DNA metabolism. The RPA gene family expanded in Arabidopsis thaliana with five phylogenetically distinct RPA1 subunits (RPA1A-E), two RPA2 (RPA2A and B), and two RPA3 (RPA3A and B). RPA1 paralogs exhibit partial redundancy and functional specialization in DNA replication (RPA1B and RPA1D), repair (RPA1C and RPA1E), and meiotic recombination (RPA1A and RPA1C). Here, we show that RPA subunits also differentially impact telomere length set point. Loss of RPA1 resets bulk telomeres at a shorter length, with a functional hierarchy for replication group over repair and meiosis group RPA1 subunits. Plants lacking RPA2A, but not RPA2B, harbor short telomeres similar to the replication group. Telomere shortening does not correlate with decreased telomerase activity or deprotection of chromosome ends in rpa mutants. However, in vitro assays show that RPA1B2A3B unfolds telomeric G-quadruplexes known to inhibit replications fork progression. We also found that ATR deficiency can partially rescue short telomeres in rpa2a mutants, although plants exhibit defects in growth and development. Unexpectedly, the telomere shortening phenotype of rpa2a mutants is completely abolished in plants lacking the RTEL1 helicase. RTEL1 has been implicated in a variety of nucleic acid transactions, including suppression of homologous recombination. Thus, the lack of telomere shortening in rpa2a mutants upon RTEL1 deletion suggests that telomere replication defects incurred by loss of RPA may be bypassed by homologous recombination. Taken together, these findings provide new insight into how RPA cooperates with replication and recombination machinery to sustain telomeric DNA.

Positive and negative regulation of telomerase access to the telomere

2000 ◽  
Vol 113 (19) ◽  
pp. 3357-3364 ◽  
Author(s):  
S.K. Evans ◽  
V. Lundblad
Keyword(s):  
Telomere Length ◽  
Mammalian Cells ◽  
Feedback System ◽  
Order Structure ◽  
Telomeric Dna ◽  
Repeat Sequences ◽  
Fundamental Part ◽  
Telomere Function ◽  
Associated Proteins ◽  
Chromosome Integrity

The protective caps on chromosome ends - known as telomeres - consist of DNA and associated proteins that are essential for chromosome integrity. A fundamental part of ensuring proper telomere function is maintaining adequate length of the telomeric DNA tract. Telomeric repeat sequences are synthesized by the telomerase reverse transcriptase, and, as such, telomerase is a central player in the maintenance of steady-state telomere length. Evidence from both yeast and mammals suggests that telomere-associated proteins positively or negatively control access of telomerase to the chromosome terminus. In yeast, positive regulation of telomerase access appears to be achieved through recruitment of the enzyme by the end-binding protein Cdc13p. In contrast, duplex-DNA-binding proteins assembled along the telomeric tract exert a feedback system that negatively modulates telomere length by limiting the action of telomerase. In mammalian cells, and perhaps also in yeast, binding of these proteins probably promotes a higher-order structure that renders the telomere inaccessible to the telomerase enzyme.

scholarly journals Alterations of DNA and Chromatin Structures at Telomeres and Genetic Instability in Mouse Cells Defective in DNA Polymerase α

2005 ◽  
Vol 25 (24) ◽  
pp. 11073-11088 ◽  
Author(s):  
Mirai Nakamura ◽  
Akira Nabetani ◽  
Takeshi Mizuno ◽  
Fumio Hanaoka ◽  
Fuyuki Ishikawa
Keyword(s):  
Telomere Length ◽  
Dna Polymerase ◽  
Temperature Sensitive ◽  
Telomeric Dna ◽  
Dna Polymerase Α ◽  
Genome Wide ◽  
Associated Proteins ◽  
Mouse Cells ◽  
The Impact ◽  
Lagging Strand

ABSTRACT Telomere length is controlled by a homeostatic mechanism that involves telomerase, telomere-associated proteins, and conventional replication machinery. Specifically, the coordinated actions of the lagging strand synthesis and telomerase have been argued. Although DNA polymerase α, an enzyme important for the lagging strand synthesis, has been indicated to function in telomere metabolism in yeasts and ciliates, it has not been characterized in higher eukaryotes. Here, we investigated the impact of compromised polymerase α activity on telomeres, using tsFT20 mouse mutant cells harboring a temperature-sensitive polymerase α mutant allele. When polymerase α was temperature-inducibly inactivated, we observed sequential events that included an initial extension of the G-tail followed by a marked increase in the overall telomere length occurring in telomerase-independent and -dependent manners, respectively. These alterations of telomeric DNA were accompanied by alterations of telomeric chromatin structures as revealed by quantitative chromatin immunoprecipitation and immunofluorescence analyses of TRF1 and POT1. Unexpectedly, polymerase α inhibition resulted in a significantly high incidence of Robertsonian chromosome fusions without noticeable increases in other types of chromosomal aberrations. These results indicate that although DNA polymerase α is essential for genome-wide DNA replication, hypomorphic activity leads to a rather specific spectrum of chromosomal abnormality.

scholarly journals The Hsp90 Molecular Chaperone Modulates Multiple Telomerase Activities

2007 ◽  
Vol 28 (1) ◽  
pp. 457-467 ◽  
Author(s):  
Oyetunji A. Toogun ◽  
Diane C. DeZwaan ◽  
Brian C. Freeman
Keyword(s):  
Dna Binding ◽  
Telomere Length ◽  
Reverse Transcription ◽  
Molecular Chaperone ◽  
Telomerase Activity ◽  
Client Protein ◽  
Telomeric Dna ◽  
Nucleotide Addition

ABSTRACT The Hsp90 molecular chaperone is a highly abundant eukaryotic molecular chaperone. While it is understood that Hsp90 modulates a significant number of proteins, the mechanistic contributions made by Hsp90 to a client protein typically are not well understood. Here we investigate the yeast Hsp90 regulatory roles with telomerase. Telomerase lengthens chromosome termini by specifically associating with single-stranded telomeric DNA and appending nucleotides by reverse transcription. We have found that the yeast Hsp90 homolog Hsp82p promotes both telomerase DNA binding and nucleotide addition properties. By isolating telomerase from different allelic backgrounds we observed distinct defects. For example, in an hsp82 T101I strain telomerase displayed decreased nucleotide processivity, whereas both DNA binding and extension activities were lowered in a G170D background. The decline in telomerase DNA binding correlated with a loss of Hsp82p association. No matter the defect, telomerase activity was recovered upon Hsp82p addition. Importantly, telomere length and telomerase telomere occupancy was yeast Hsp90 dependent. Taken together, our results indicate that Hsp82p promotes telomerase DNA association and facilitates DNA extension once telomerase is engaged with the DNA.

scholarly journals Telomerase activity can mediate the effects of growth on telomeres during post-natal development in a wild bird

2021 ◽  
Author(s):  
Jose C. Noguera ◽  
Alberto Velando
Keyword(s):  
Telomere Length ◽  
Bird Species ◽  
Growth Period ◽  
Postnatal Growth ◽  
Telomerase Activity ◽  
Activity Levels ◽  
Telomere Attrition ◽  
Somatic Tissues ◽  
Negative Effect ◽  
Larus Michahellis

In wild animals, telomere attrition during early development has been linked with several fitness penalties throughout life. Telomerase enzyme can elongate telomeres, but it is generally assumed that its activity is suppressed in most somatic tissues upon birth. However, recent evidence suggests that this may not be the rule for long-lived bird species. We have therefore investigated whether telomerase activity is maintained during the postnatal growth period in a wild yellow-legged gull (Larus michahellis) population. Our results indicate that telomerase activity is not negligible in the blood cells, but activity levels sharply decline from hatching to fledging following a similar pattern to that observed in telomere length. Our results further suggest that the observed variation in telomere length may be the result of a negative effect of fast growth on telomerase activity, thus providing a new mechanism through which growth rates may affect telomere dynamics and potentially life-history trajectories.

Telomerase activity and telomere length of peripheral blood mononuclear cells in SLE patients

Lupus ◽  
2003 ◽  
Vol 12 (8) ◽  
pp. 591-599 ◽  
Author(s):  
Daitaro Kurosaka ◽  
Jun Yasuda ◽  
Ken Yoshida ◽  
Toru Yokoyama ◽  
Yoshinori Ozawa ◽  
...  
Keyword(s):  
Telomere Length ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Telomerase Activity ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

scholarly journals Human Telomerase and Its Regulation

2002 ◽  
Vol 66 (3) ◽  
pp. 407-425 ◽  
Author(s):  
Yu-Sheng Cong ◽  
Woodring E. Wright ◽  
Jerry W. Shay
Keyword(s):  
Dna Sequences ◽  
Molecular Mechanisms ◽  
Telomerase Activity ◽  
Cellular Aging ◽  
Telomeric Dna ◽  
Associated Proteins ◽  
Functional Complex ◽  
Length Regulation ◽  
Normal Human ◽  
Human Telomerase

SUMMARY The telomere is a special functional complex at the end of linear eukaryotic chromosomes, consisting of tandem repeat DNA sequences and associated proteins. It is essential for maintaining the integrity and stability of linear eukaryotic genomes. Telomere length regulation and maintenance contribute to normal human cellular aging and human diseases. The synthesis of telomeres is mainly achieved by the cellular reverse transcriptase telomerase, an RNA-dependent DNA polymerase that adds telomeric DNA to telomeres. Expression of telomerase is usually required for cell immortalization and long-term tumor growth. In humans, telomerase activity is tightly regulated during development and oncogenesis. The modulation of telomerase activity may therefore have important implications in antiaging and anticancer therapy. This review describes the currently known components of the telomerase complex and attempts to provide an update on the molecular mechanisms of human telomerase regulation.

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