scholarly journals Localization of hRad9, hHus1, hRad1, and hRad17 and Caffeine-sensitive DNA Replication at the Alternative Lengthening of Telomeres-associated Promyelocytic Leukemia Body

2004 ◽  
Vol 279 (24) ◽  
pp. 25849-25857 ◽  
Author(s):  
Akira Nabetani ◽  
Osamu Yokoyama ◽  
Fuyuki Ishikawa
Keyword(s):  
Dna Replication ◽  
Promyelocytic Leukemia ◽  
Alternative Lengthening Of Telomeres ◽  
Alternative Lengthening

scholarly journals Suppression of Alternative Lengthening of Telomeres by Sp100-Mediated Sequestration of the MRE11/RAD50/NBS1 Complex

2005 ◽  
Vol 25 (7) ◽  
pp. 2708-2721 ◽  
Author(s):  
Wei-Qin Jiang ◽  
Ze-Huai Zhong ◽  
Jeremy D. Henson ◽  
Axel A. Neumann ◽  
Andy C.-M. Chang ◽  
...  
Keyword(s):  
Dna Replication ◽  
Telomere Length ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Population Doubling ◽  
Telomeric Dna ◽  
Alternative Lengthening Of Telomeres ◽  
Telomere Shortening ◽  
Alternative Lengthening ◽  
Length Changes

ABSTRACT Approximately 10% of cancers overall use alternative lengthening of telomeres (ALT) instead of telomerase to prevent telomere shortening, and ALT is especially common in astrocytomas and various types of sarcomas. The hallmarks of ALT in telomerase-negative cancer cells include a unique pattern of telomere length heterogeneity, rapid changes in individual telomere lengths, and the presence of ALT-associated promyelocytic leukemia bodies (APBs) containing telomeric DNA and proteins involved in telomere binding, DNA replication, and recombination. The ALT mechanism appears to involve recombination-mediated DNA replication, but the molecular details are largely unknown. In telomerase-null Saccharomyces cerevisiae, an analogous survivor mechanism is dependent on the RAD50 gene. We demonstrate here that overexpression of Sp100, a constituent of promyelocytic leukemia nuclear bodies, sequestered the MRE11, RAD50, and NBS1 recombination proteins away from APBs. This resulted in repression of the ALT mechanism, as evidenced by progressive telomere shortening at 121 bp per population doubling, a rate within the range found in telomerase-negative normal cells, suppression of rapid telomere length changes, and suppression of APB formation. Spontaneously generated C-terminally truncated Sp100 that did not sequester the MRE11, RAD50, and NBS1 proteins failed to inhibit ALT. These findings identify for the first time proteins that are required for the ALT mechanism.

scholarly journals Coexistence of Alternative Lengthening of Telomeres and Telomerase in hTERT-Transfected GM847 Cells

2001 ◽  
Vol 21 (12) ◽  
pp. 3862-3875 ◽  
Author(s):  
Kilian Perrem ◽  
Lorel M. Colgin ◽  
Axel A. Neumann ◽  
Thomas R. Yeager ◽  
Roger R. Reddel
Keyword(s):  
Cell Line ◽  
Telomerase Activity ◽  
Promyelocytic Leukemia ◽  
Tumor Cell Lines ◽  
Hybrid Cells ◽  
Alternative Lengthening Of Telomeres ◽  
Positive Tumor Cell ◽  
Alternative Lengthening ◽  
Pml Bodies ◽  
Population Doublings

ABSTRACT It has been shown previously that some immortalized human cells maintain their telomeres in the absence of significant levels of telomerase activity by a mechanism referred to as alternative lengthening of telomeres (ALT). Cells utilizing ALT have telomeres of very heterogeneous length, ranging from very short to very long. Here we report the effect of telomerase expression in the ALT cell line GM847. Expression of exogenous hTERT in GM847 (GM847/hTERT) cells resulted in lengthening of the shortest telomeres; this is the first evidence that expression of hTERT in ALT cells can induce telomerase that is active at the telomere. However, rapid fluctuation in telomere length still occurred in the GM847/hTERT cells after more than 100 population doublings. Very long telomeres and ALT-associated promyelocytic leukemia (PML) bodies continued to be generated, indicating that telomerase activity induced by exogenous hTERT did not abolish the ALT mechanism. In contrast, when the GM847 cell line was fused with two different telomerase-positive tumor cell lines, the ALT phenotype was repressed in each case. These hybrid cells were telomerase positive, and the telomeres decreased in length, very rapidly at first and then at the rate seen in telomerase-negative normal cells. Additionally, ALT-associated PML bodies disappeared. After the telomeres had shortened sufficiently, they were maintained at a stable length by telomerase. Together these data indicate that the telomerase-positive cells contain a factor that represses the ALT mechanism but that this factor is unlikely to be telomerase. Further, the transfection data indicate that ALT and telomerase can coexist in the same cells.

scholarly journals Identification of Key Proteins in the Alternative Lengthening of Telomeres Associated Promyelocytic Leukemia Nuclear Bodies

2021 ◽  
Author(s):  
Isaac Armendáriz-Castillo ◽  
Katherine Hidalgo-Fernández ◽  
Andy Pérez-Villa ◽  
Jennyfer García-Cárdenas ◽  
Andrés López-Cortés ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Alternative Lengthening Of Telomeres ◽  
Pml Nuclear Bodies ◽  
Alternative Lengthening

One of the hallmarks of the Alternative Lengthening of Telomeres (ALT) is the association with Promyelocytic Leukemia (PML) Nuclear Bodies, known as APBs. In the last years, APBs have been described as the main place where telomeric extension occurs in ALT positive cancer cell lines. A different set of proteins have been associated with APBs function, however, the molecular mechanisms behind their assembly, colocalization, and clustering of telomeres, among others, remain unclear. To improve the understanding of APBs in the ALT pathway, we integrated multi-omics analyses to evaluate genomic, transcriptomic and proteomic alterations, and functional interactions of 71 APBs-related genes/proteins in 32 PanCancer Atlas studies from The Cancer Genome Atlas Consortium (TCGA). As a result, we identified 13 key proteins which showed distinctive mutations, interactions, and functional enrichment patterns across all the cancer types and proposed this set of proteins as candidates for future ex vivo and in vivo analyses that will validate these proteins to improve the understanding of the ALT pathway, fill the current research gap about APBs function and their role in ALT, and be considered as potential therapeutic targets for the diagnosis and treatment of ALT positive cancers in the future.

scholarly journals TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chuanle Wang ◽  
Zhou Songyang ◽  
Yan Huang
Keyword(s):  
Cell Growth ◽  
Tumor Cells ◽  
Sister Chromatid ◽  
Sister Chromatid Exchange ◽  
Chromatin Modification ◽  
Histone Methyltransferase ◽  
Promyelocytic Leukemia ◽  
Telomeric Dna ◽  
Alternative Lengthening Of Telomeres ◽  
Alternative Lengthening

Abstract Background About 10–15% of tumor cells extend telomeres through the alternative lengthening of telomeres (ALT) mechanism, which is a recombination-dependent replication pathway. It is generally believed that ALT cells are related to the chromatin modification of telomeres. However, the mechanism of ALT needs to be further explored. Results Here we found that TRIM28/KAP1 is preferentially located on the telomeres of ALT cells and interacts with telomeric shelterin/telosome complex. Knocking down TRIM28 in ALT cells delayed cell growth, decreased the level of C-circle which is one kind of extrachromosomal circular telomeric DNA, increased the frequency of ALT-associated promyelocytic leukemia bodies (APBs), led to telomere prolongation and increased the telomere sister chromatid exchange in ALT cells. Mechanistically, TRIM28 protects telomere histone methyltransferase SETDB1 from degradation, thus maintaining the H3K9me3 heterochromatin state of telomere DNA. Conclusions Our work provides a model that TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation. In general, our results reveal the mechanism of telomere heterochromatin maintenance and its effect on ALT, and TRIM28 may serve as a target for the treatment of ALT tumor cells.

scholarly journals Nuclear body phase separation drives telomere clustering in ALT cancer cells

2020 ◽  
Vol 31 (18) ◽  
pp. 2048-2056 ◽  
Author(s):  
Huaiying Zhang ◽  
Rongwei Zhao ◽  
Jason Tones ◽  
Michel Liu ◽  
Robert L. Dilley ◽  
...  
Keyword(s):  
Dna Repair ◽  
Phase Separation ◽  
Cancer Cells ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Telomere Elongation ◽  
Alternative Lengthening ◽  
Induce Phase Separation ◽  
Induce Phase

A chemical dimerization approach is developed to induce phase separation of APB nuclear bodies involved in telomere elongation in alternative lengthening of telomeres (ALT) cancer cells. It reveals that ALT telomere-associated promyelocytic leukemia nuclear body (APB) fusion leads to telomere clustering to provide templates for homology-directed telomere synthesis, an ability that is decoupled from APB function in enriching DNA repair factors.

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