scholarly journals Induction of alternative lengthening of telomeres-associated PML bodies by p53/p21 requires HP1 proteins

2009 ◽  
Vol 185 (5) ◽  
pp. 797-810 ◽  
Author(s):  
Wei-Qin Jiang ◽  
Ze-Huai Zhong ◽  
Akira Nguyen ◽  
Jeremy D. Henson ◽  
Christian D. Toouli ◽  
...  
Keyword(s):  
Growth Arrest ◽  
Nuclear Bodies ◽  
Activity Level ◽  
Heterochromatin Protein 1 ◽  
Alternative Lengthening Of Telomeres ◽  
Heterochromatin Protein ◽  
Alternative Lengthening ◽  
Pml Bodies ◽  
A Cell ◽  
Hp1 Proteins

Alternative lengthening of telomeres (ALT) is a recombination-mediated process that maintains telomeres in telomerase-negative cancer cells. In asynchronously dividing ALT-positive cell populations, a small fraction of the cells have ALT-associated promyelocytic leukemia nuclear bodies (APBs), which contain (TTAGGG)n DNA and telomere-binding proteins. We found that restoring p53 function in ALT cells caused p21 up-regulation, growth arrest/senescence, and a large increase in cells containing APBs. Knockdown of p21 significantly reduced p53-mediated induction of APBs. Moreover, we found that heterochromatin protein 1 (HP1) is present in APBs, and knockdown of HP1α and/or HP1γ prevented p53-mediated APB induction, which suggests that HP1-mediated chromatin compaction is required for APB formation. Therefore, although the presence of APBs in a cell line or tumor is an excellent qualitative marker for ALT, the association of APBs with growth arrest/senescence and with “closed” telomeric chromatin, which is likely to repress recombination, suggests there is no simple correlation between ALT activity level and the number of APBs or APB-positive cells.

scholarly journals Heterochromatin Protein 1 (HP1) Proteins Do Not Drive Pericentromeric Cohesin Enrichment in Human Cells

PLoS ONE ◽  
2009 ◽  
Vol 4 (4) ◽  
pp. e5118 ◽  
Author(s):  
Ángel Serrano ◽  
Miriam Rodríguez-Corsino ◽  
Ana Losada
Keyword(s):  
Human Cells ◽  
Heterochromatin Protein 1 ◽  
Heterochromatin Protein ◽  
Hp1 Proteins

scholarly journals Evidence for alternative lengthening of telomeres in liposarcomas in the absence of ALT-associated PML bodies

2008 ◽  
Vol 122 (11) ◽  
pp. 2414-2421 ◽  
Author(s):  
Jennie N. Jeyapalan ◽  
Aaron Mendez-Bermudez ◽  
Nadia Zaffaroni ◽  
Yuri E. Dubrova ◽  
Nicola J. Royle
Keyword(s):  
Alternative Lengthening Of Telomeres ◽  
Alternative Lengthening ◽  
Pml Bodies

scholarly journals Pericentromeric Heterochromatin Domains Are Maintained without Accumulation of HP1

2007 ◽  
Vol 18 (4) ◽  
pp. 1464-1471 ◽  
Author(s):  
Julio Mateos-Langerak ◽  
Maartje C. Brink ◽  
Martijn S. Luijsterburg ◽  
Ineke van der Kraan ◽  
Roel van Driel ◽  
...  
Keyword(s):  
Histone H3 ◽  
Dominant Negative ◽  
Pericentromeric Heterochromatin ◽  
Heterochromatin Protein 1 ◽  
Dapi Staining ◽  
Heterochromatin Protein ◽  
3T3 Fibroblasts ◽  
Heterochromatin Structure ◽  
Hp1 Proteins

The heterochromatin protein 1 (HP1) family is thought to be an important structural component of heterochromatin. HP1 proteins bind via their chromodomain to nucleosomes methylated at lysine 9 of histone H3 (H3K9me). To investigate the role of HP1 in maintaining heterochromatin structure, we used a dominant negative approach by expressing truncated HP1α or HP1β proteins lacking a functional chromodomain. Expression of these truncated HP1 proteins individually or in combination resulted in a strong reduction of the accumulation of HP1α, HP1β, and HP1γ in pericentromeric heterochromatin domains in mouse 3T3 fibroblasts. The expression levels of HP1 did not change. The apparent displacement of HP1α, HP1β, and HP1γ from pericentromeric heterochromatin did not result in visible changes in the structure of pericentromeric heterochromatin domains, as visualized by DAPI staining and immunofluorescent labeling of H3K9me. Our results show that the accumulation of HP1α, HP1β, and HP1γ at pericentromeric heterochromatin domains is not required to maintain DAPI-stained pericentromeric heterochromatin domains and the methylated state of histone H3 at lysine 9 in such heterochromatin domains.

scholarly journals Heterochromatin protein 1 is recruited to various types of DNA damage

2009 ◽  
Vol 185 (4) ◽  
pp. 577-586 ◽  
Author(s):  
Martijn S. Luijsterburg ◽  
Christoffel Dinant ◽  
Hannes Lans ◽  
Jan Stap ◽  
Elzbieta Wiernasz ◽  
...  
Keyword(s):  
Dna Damage ◽  
Uv Light ◽  
High Sensitivity ◽  
Heterochromatin Protein 1 ◽  
Heterochromatin Protein ◽  
Strand Breaks ◽  
Essential Components ◽  
Associated Proteins ◽  
Chromo Shadow Domain ◽  
Hp1 Proteins

Heterochromatin protein 1 (HP1) family members are chromatin-associated proteins involved in transcription, replication, and chromatin organization. We show that HP1 isoforms HP1-α, HP1-β, and HP1-γ are recruited to ultraviolet (UV)-induced DNA damage and double-strand breaks (DSBs) in human cells. This response to DNA damage requires the chromo shadow domain of HP1 and is independent of H3K9 trimethylation and proteins that detect UV damage and DSBs. Loss of HP1 results in high sensitivity to UV light and ionizing radiation in the nematode Caenorhabditis elegans, indicating that HP1 proteins are essential components of DNA damage response (DDR) systems. Analysis of single and double HP1 mutants in nematodes suggests that HP1 homologues have both unique and overlapping functions in the DDR. Our results show that HP1 proteins are important for DNA repair and may function to reorganize chromatin in response to damage.

Evidence for Alternative Lengthening of Telomeres in Chronic Lymphocytic Leukemia Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1179-1179
Author(s):  
Rajendra N. Damle ◽  
Taraneh Banapour ◽  
Cristina Sison ◽  
Steven L. Allen ◽  
Kanti R. Rai ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Telomerase Activity ◽  
Lymphocytic Leukemia ◽  
Nuclear Bodies ◽  
Telomere Maintenance ◽  
Osteosarcoma Cell ◽  
Clonal Deletion ◽  
Alternative Lengthening Of Telomeres ◽  
Alternative Lengthening ◽  
V Genes

Abstract Telomere shortening is a consequence of repetitive clonal replication and leads to clonal deletion unless DNA extension and repair occur. All tumors must circumvent this problem by up-regulating mechanisms that lead to chromosomal lengthening. Two mechanisms have been identified that maintain chromosome ends- telomerase that does so by reverse transcription and alternative lengthening of telomeres (ALT) that occurs by homologous recombination. The latter function is characterized by the presence of promyelocytic leukemia protein-associated nuclear bodies (PML-NBs) and the presence of PML-NB is used to mark cells that use this process. B cell Chronic lymphocytic leukemia (B-CLL) cells with unmutated Ig V genes have shorter mean telomere lengths compared with those exhibiting mutated Ig V genes. In addition, cells with unmutated Ig V genes demonstrate more telomerase activity than their mutated counterparts. The mutated cases show long and heterogeneously elongated telomeres in spite of the absence, in most cases, of detectable telomerase activity. Therefore we determined whether the ALT pathway plays a role in telomere maintenance in B-CLL, using a monoclonal anti-PML antibody and a flow-cytometric assay for assessment of PML protein. Telomerase-expressing Jurkat T cells and murine fibroblasts-L cells served as negative controls for PML staining, whereas the ALT positive Osteosarcoma cell line U2-OS served as a positive control. In a cohort of 20 B-CLL cases, PML protein was detected in all cases regardless of Ig V mutation status. In addition, a similar percentage of cells within the clones contained PML (10 - 90% of the members of unmutated clones and 11–96% of mutated clones), whereas peripheral blood B cells from 6/6 elderly normal donors did not show any PML staining. PML expression was compared with telomere length and telomerase activity in the same cases. The percentage of cells showing PML expression inversely correlated with telomerase activity (r= −0.58; p=0.029). Although in most published reports telomere maintenance by ALT occurs in the absence of telomerase activity, we found ALT (as suggested by PML positive cells) in cells with telomerase activity (detected by the standard TRAP assay). Thus, B-CLL cases can express PML bodies and some B-CLL cells can contain both PML-NB and express telomerase activity. These findings suggest that B-CLL cells can use two distinct mechanisms to assure telomere maintenance and perpetuate clonal survival and expansion.

scholarly journals Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Timothy P. Lippert ◽  
Paulina Marzec ◽  
Aurora I. Idilli ◽  
Grzegorz Sarek ◽  
Aleksandra Vancevska ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Telomere Maintenance ◽  
Alternative Lengthening Of Telomeres ◽  
Telomere Shortening ◽  
Alternative Lengthening ◽  
A Cell ◽  
Infected Cells ◽  
Break Induced Replication ◽  
Alt Activity

AbstractTo achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. ~85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining ~15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi’s sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours.

scholarly journals Telomere length heterogeneity in ALT cells is maintained by PML-dependent localization of the BTR complex to telomeres

2020 ◽  
Author(s):  
Taylor K Loe ◽  
Julia Su Zhou Li ◽  
Yuxiang Zhang ◽  
Benura Azeroglu ◽  
Michael Nicholas Boddy ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Nuclear Bodies ◽  
Independent Manner ◽  
Telomere Repeat ◽  
Pml Nuclear Bodies ◽  
Alternative Lengthening ◽  
Pml Bodies ◽  
Independent Mechanism ◽  
Linear Chromosomes ◽  
Alt Activity

ABSTRACTTelomeres consist of TTAGGG repeats bound by protein complexes that serve to protect the natural end of linear chromosomes. Most cells maintain telomere repeat lengths by utilizing the enzyme telomerase, although there are some cancer cells that use a telomerase-independent mechanism of telomere extension, termed Alternative Lengthening of Telomeres (ALT). Cells that employ ALT are characterized, in part, by the presence of specialized PML nuclear bodies called ALT-associated PML-Bodies (APBs). APBs localize to and cluster telomeric ends together with telomeric and DNA damage factors, which led to the proposal that these bodies act as a platform on which ALT can occur. However, the necessity of APBs and their function in the ALT pathway has remained unclear. Here, we used CRISPR/Cas9 to delete PML and APB components from ALT-positive cells to cleanly define the function of APBs in ALT. We find that PML is required for the ALT mechanism, and that this necessity stems from APBs’ role in localizing the BLM-TOP3A-RMI (BTR) complex to ALT telomere ends. Strikingly, recruitment of the BTR complex to telomeres in a PML-independent manner bypasses the need for PML in the ALT pathway, suggesting that BTR localization to telomeres is sufficient to sustain ALT activity.

scholarly journals ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner

PLoS ONE ◽  
2018 ◽  
Vol 13 (9) ◽  
pp. e0204159 ◽  
Author(s):  
Jacqueline A. Brosnan-Cashman ◽  
Ming Yuan ◽  
Mindy K. Graham ◽  
Anthony J. Rizzo ◽  
Kaylar M. Myers ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Glioma Cell ◽  
Human Glioma ◽  
Alternative Lengthening Of Telomeres ◽  
Human Glioma Cell ◽  
Alternative Lengthening ◽  
Glioma Cell Lines ◽  
Specific Manner ◽  
A Cell

scholarly journals The level of activity of the alternative lengthening of telomeres correlates with patient age in IDH-mutant ATRX-loss-of-expression anaplastic astrocytomas

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Nathalie Grandin ◽  
◽  
Bruno Pereira ◽  
Camille Cohen ◽  
Pauline Billard ◽  
...  
Keyword(s):  
Activity Level ◽  
Telomere Maintenance ◽  
Alternative Lengthening Of Telomeres ◽  
Patient Age ◽  
Alternative Lengthening ◽  
Level Of Activity ◽  
Patient Âgé ◽  
Diffuse Gliomas ◽  
Cancer Types ◽  
Alt Activity

Abstract All cancer cells need to maintain functional telomeres to sustain continuous cell division and proliferation. In human diffuse gliomas, functional telomeres are maintained due either to reactivation of telomerase expression, the main pathway in most cancer types, or to activation of a mechanism called the alternative lengthening of telomeres (ALT). The presence of IDH1/2 mutations (IDH-mutant) together with loss of ATRX expression (ATRX-lost) are frequently associated with ALT in diffuse gliomas. However, detection of ALT, and a fortiori its quantification, are rarely, if ever, measured in neuropathology laboratories. We measured the level of ALT activity using the previously described quantitative “C-circle” assay and analyzed it in a well characterized cohort of 104 IDH-mutant and ATRX-lost adult diffuse gliomas. We report that in IDH-mutant ATRX-lost anaplastic astrocytomas, the intensity of ALT was inversely correlated with age (p < 0.001), the younger the patient, the higher the intensity of ALT. Strikingly, glioblastomas having progressed from anaplastic astrocytomas did not exhibit this correlation. ALT activity level in the tumor did not depend on telomere length in healthy tissue cells from the same patient. In summary, we have uncovered the existence, in anaplastic astrocytomas but not in glioblastomas with the same IDH and ATRX mutations, of a correlation between patient age and the level of activity of ALT, a telomerase-independent pathway of telomere maintenance.

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