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.

scholarly journals Liquid condensation drives telomere clustering during ALT

2019 ◽  
Author(s):  
Huaiying Zhang ◽  
Michel Liu ◽  
Robert Dilley ◽  
David M. Chenoweth ◽  
Roger A. Greenberg ◽  
...  
Keyword(s):  
Dna Repair ◽  
Chemical Composition ◽  
Cancer Cells ◽  
Material Properties ◽  
General Framework ◽  
Cellular Functions ◽  
Telomere Elongation ◽  
Alternative Lengthening ◽  
Chemically Induced ◽  
Chemically Induced Dimerization

AbstractTelomerase-free cancer cells employ a recombination-based alternative lengthening of telomeres (ALT) pathway that depends on ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs), whose function is unclear. We find that APBs behave as liquid condensates, suggesting two potential mechanisms to promote telomere elongation: condensation to enrich DNA repair factors for telomere synthesis and coalescence to cluster telomeres to provide repair templates. Using chemically-induced dimerization, we show that telomere sumoylation nucleates APB condensation via SUMO-SIM (SUMO interaction motif) interactions and clusters telomeres. The induced APBs lack DNA repair factors, indicating that these factors are clients recruited to the APB scaffold rather than components that drive condensation. Telomere clustering, however, relies only on liquid properties of the condensate, as an alternative condensation chemistry also induces clustering. Our results demonstrate how the material properties and chemical composition of APBs independently contribute to ALT, suggesting a general framework for how liquid condensates promote cellular functions.

scholarly journals Dynamics of Telomeres and Promyelocytic Leukemia Nuclear Bodies in a Telomerase-negative Human Cell Line

2009 ◽  
Vol 20 (7) ◽  
pp. 2070-2082 ◽  
Author(s):  
Thibaud Jegou ◽  
Inn Chung ◽  
Gerrit Heuvelman ◽  
Malte Wachsmuth ◽  
Sabine M. Görisch ◽  
...  
Keyword(s):  
Cell Line ◽  
Human Cell Line ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Nuclear Space ◽  
Telomere Repeat ◽  
Lac Operator ◽  
Alternative Lengthening ◽  
Promyelocytic Leukemia Nuclear Bodies ◽  
Negative Tumor

Telomerase-negative tumor cells maintain their telomeres via an alternative lengthening of telomeres (ALT) mechanism. This process involves the association of telomeres with promyelocytic leukemia nuclear bodies (PML-NBs). Here, the mobility of both telomeres and PML-NBs as well as their interactions were studied in human U2OS osteosarcoma cells, in which the ALT pathway is active. A U2OS cell line was constructed that had lac operator repeats stably integrated adjacent to the telomeres of chromosomes 6q, 11p, and 12q. By fluorescence microscopy of autofluorescent LacI repressor bound to the lacO arrays the telomere mobility during interphase was traced and correlated with the telomere repeat length. A confined diffusion model was derived that describes telomere dynamics in the nucleus on the time scale from seconds to hours. Two telomere groups were identified that differed with respect to the nuclear space accessible to them. Furthermore, translocations of PML-NBs relative to telomeres and their complexes with telomeres were evaluated. Based on these studies, a model is proposed in which the shortening of telomeres results in an increased mobility that could facilitate the formation of complexes between telomeres and PML-NBs.

scholarly journals ALT: A Multi-Faceted Phenomenon

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 133 ◽  
Author(s):  
Aurore Sommer ◽  
Nicola J. Royle
Keyword(s):  
Molecular Markers ◽  
Cancer Cells ◽  
Targeted Therapies ◽  
Sequence Variation ◽  
Telomere Maintenance ◽  
Hallmarks Of Cancer ◽  
Telomere Elongation ◽  
Maintenance Mechanism ◽  
Alternative Lengthening ◽  
Made In

One of the hallmarks of cancer cells is their indefinite replicative potential, made possible by the activation of a telomere maintenance mechanism (TMM). The majority of cancers reactivate the reverse transcriptase, telomerase, to maintain their telomere length but a minority (10% to 15%) utilize an alternative lengthening of telomeres (ALT) pathway. Here, we review the phenotypes and molecular markers specific to ALT, and investigate the significance of telomere mutations and sequence variation in ALT cell lines. We also look at the recent advancements in understanding the different mechanisms behind ALT telomere elongation and finally, the progress made in identifying potential ALT-targeted therapies, including those already in use for the treatment of both hematological and solid tumors.

Does dynamic vulcanization induce phase separation?

Soft Matter ◽  
2014 ◽  
Vol 10 (30) ◽  
pp. 5550-5558 ◽  
Author(s):  
Mohammad Mahdi Abolhasani ◽  
Fatemeh Zarejousheghani ◽  
Minoo Naebe ◽  
Qipeng Guo
Keyword(s):  
Phase Separation ◽  
Crosslink Density ◽  
Vinylidene Fluoride ◽  
Dynamic Vulcanization ◽  
Miscible Blends ◽  
Poly Vinylidene Fluoride ◽  
Induce Phase Separation ◽  
Induce Phase

Immiscible and miscible blends of poly(vinylidene fluoride) (PVDF) and acrylic rubber (ACM) were subjected to dynamic vulcanization to investigate the effect of crosslink density on phase separation.

scholarly journals Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR

2006 ◽  
Vol 175 (1) ◽  
pp. 55-66 ◽  
Author(s):  
Graham Dellaire ◽  
Reagan W. Ching ◽  
Kashif Ahmed ◽  
Farid Jalali ◽  
Kenneth C.K. Tse ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cellular Response ◽  
Cell Cycle Progression ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
S Phase ◽  
Nuclear Bodies ◽  
Structural Basis ◽  
Loss Of Function

The promyelocytic leukemia (PML) nuclear body (NB) is a dynamic subnuclear compartment that is implicated in tumor suppression, as well as in the transcription, replication, and repair of DNA. PML NB number can change during the cell cycle, increasing in S phase and in response to cellular stress, including DNA damage. Although topological changes in chromatin after DNA damage may affect the integrity of PML NBs, the molecular or structural basis for an increase in PML NB number has not been elucidated. We demonstrate that after DNA double-strand break induction, the increase in PML NB number is based on a biophysical process, as well as ongoing cell cycle progression and DNA repair. PML NBs increase in number by a supramolecular fission mechanism similar to that observed in S-phase cells, and which is delayed or inhibited by the loss of function of NBS1, ATM, Chk2, and ATR kinase. Therefore, an increase in PML NB number is an intrinsic element of the cellular response to DNA damage.

scholarly journals Arsenic-Induced SUMO-Dependent Recruitment of RNF4 into PML Nuclear Bodies

2010 ◽  
Vol 21 (23) ◽  
pp. 4227-4239 ◽  
Author(s):  
Marie-Claude Geoffroy ◽  
Ellis G. Jaffray ◽  
Katherine J. Walker ◽  
Ronald T. Hay
Keyword(s):  
Retinoic Acid Receptor ◽  
E3 Ligase ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Dependent Manner ◽  
Nuclear Trafficking ◽  
Sumo Modification ◽  
Ubiquitin E3 Ligase ◽  
Pml Nuclear Bodies

In acute promyelocytic leukemia (APL), the promyelocytic leukemia (PML) protein is fused to the retinoic acid receptor alpha (RAR). Arsenic is an effective treatment for this disease as it induces SUMO-dependent ubiquitin-mediated proteasomal degradation of the PML-RAR fusion protein. Here we analyze the nuclear trafficking dynamics of PML and its SUMO-dependent ubiquitin E3 ligase, RNF4 in response to arsenic. After administration of arsenic, PML immediately transits into nuclear bodies where it undergoes SUMO modification. This initial recruitment of PML into nuclear bodies is not dependent on RNF4, but RNF4 quickly follows PML into the nuclear bodies where it is responsible for ubiquitylation of SUMO-modified PML and its degradation by the proteasome. While arsenic restricts the mobility of PML, FRAP analysis indicates that RNF4 continues to rapidly shuttle into PML nuclear bodies in a SUMO-dependent manner. Under these conditions FRET studies indicate that RNF4 interacts with SUMO in PML bodies but not directly with PML. These studies indicate that arsenic induces the rapid reorganization of the cell nucleus by SUMO modification of nuclear body-associated PML and uptake of the ubiquitin E3 ligase RNF4 leading to the ubiquitin-mediated degradation of PML.

scholarly journals Role of Promyelocytic Leukemia (Pml) Sumolation in Nuclear Body Formation, 11s Proteasome Recruitment, and as2O3-Induced Pml or Pml/Retinoic Acid Receptor α Degradation

2001 ◽  
Vol 193 (12) ◽  
pp. 1361-1372 ◽  
Author(s):  
Valérie Lallemand-Breitenbach ◽  
Jun Zhu ◽  
Francine Puvion ◽  
Marcel Koken ◽  
Nicole Honoré ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Nuclear Matrix ◽  
Viral Infections ◽  
Retinoic Acid Receptor ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Acid Receptor ◽  
Pml Nuclear Bodies ◽  
Retinoic Acid Receptor Α

Promyelocytic leukemia (PML) is the organizer of nuclear matrix domains, PML nuclear bodies (NBs), with a proposed role in apoptosis control. In acute promyelocytic leukemia, PML/retinoic acid receptor (RAR) α expression disrupts NBs, but therapies such as retinoic acid or arsenic trioxide (As2O3) restore them. PML is conjugated by the ubiquitin-related peptide SUMO-1, a process enhanced by As2O3 and proposed to target PML to the nuclear matrix. We demonstrate that As2O3 triggers the proteasome-dependent degradation of PML and PML/RARα and that this process requires a specific sumolation site in PML, K160. PML sumolation is dispensable for its As2O3-induced matrix targeting and formation of primary nuclear aggregates, but is required for the formation of secondary shell-like NBs. Interestingly, only these mature NBs harbor 11S proteasome components, which are further recruited upon As2O3 exposure. Proteasome recruitment by sumolated PML only likely accounts for the failure of PML-K160R to be degraded. Therefore, studying the basis of As2O3-induced PML/RARα degradation we show that PML sumolation directly or indirectly promotes its catabolism, suggesting that mature NBs could be sites of intranuclear proteolysis and opening new insights into NB alterations found in viral infections or transformation.

scholarly journals Promyelocytic leukemia nuclear body (PML-NB) -free intranuclear milieu facilitates development of oocytes in mice

2021 ◽  
Author(s):  
Osamu Udagawa ◽  
Ayaka Kato-Udagawa ◽  
Seishiro Hirano
Keyword(s):  
Multiple Stressors ◽  
Liquid Droplet ◽  
Biological Activities ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Oocyte Nucleus ◽  
Oocyte Growth ◽  
Nuclear Maturation ◽  
Pml Nuclear Bodies

Promyelocytic leukemia (PML) nuclear bodies (PML-NBs), a class of membrane-less organelles in cells, are involved in multiple biological activities and are present throughout cells of adult organisms. Although the oocyte nucleus is an active region for the flux of multiple non-membranous organelles, PML-NBs have been predicted to be absent from oocytes. Here, we show that the deliberate assembly of PML-NBs during oocyte growth preferentially sequestered Small Ubiquitin-related Modifier (SUMO) protein from the nucleoplasm. SUMO not only was involved in the regulation of oocyte nuclear maturation but also was committed to the response, mediated by liquid droplet formation, to multiple stressors including nucleolar stress and proteotoxic stresses. Exogenous assembly of PML-NBs in the nucleus of oocytes affected the efficiency of the response of SUMO. These observations suggest that the PML-NB-free intranuclear milieu ensures that a reserve of SUMO remains available for emergent responses in oocyte development. This work demonstrated a benefit of the PML-NB-free intranuclear milieu, namely the ability to redirect the flux of SUMO otherwise needed to control PML-NB dynamics.

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