Liquid condensation drives telomere clustering during ALT

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.

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Nuclear body phase separation drives telomere clustering in ALT cancer cells

Molecular Biology of the Cell ◽

10.1091/mbc.e19-10-0589 ◽

2020 ◽

Vol 31 (18) ◽

pp. 2048-2056 ◽

Cited By ~ 6

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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ALT: A Multi-Faceted Phenomenon

Genes ◽

10.3390/genes11020133 ◽

2020 ◽

Vol 11 (2) ◽

pp. 133 ◽

Cited By ~ 4

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.

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Pharmacological targeting of differential DNA repair, radio-sensitizes WRN-deficient cancer cells in vitro and in vivo

Biochemical Pharmacology ◽

10.1016/j.bcp.2021.114450 ◽

2021 ◽

Vol 186 ◽

pp. 114450

Author(s):

Pooja Gupta ◽

Bhaskar Saha ◽

Subrata Chattopadhyay ◽

Birija Sankar Patro

Keyword(s):

Dna Repair ◽

Cancer Cells

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Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells

Pharmaceuticals ◽

10.3390/ph14070624 ◽

2021 ◽

Vol 14 (7) ◽

pp. 624

Author(s):

Valentina Corvaglia ◽

Imène Ait Mohamed Amar ◽

Véronique Garambois ◽

Stéphanie Letast ◽

Aurélie Garcin ◽

...

Keyword(s):

Cancer Cells ◽

Topoisomerase I ◽

Ovarian Cancer Cells ◽

Cellular Functions ◽

Antibody Drug Conjugate ◽

Her2 Positive ◽

Dna Topoisomerase ◽

Antibody Conjugate ◽

A Site

Inhibition of protein–DNA interactions represents an attractive strategy to modulate essential cellular functions. We reported the synthesis of unique oligoamide-based foldamers that adopt single helical conformations and mimic the negatively charged phosphate moieties of B-DNA. These mimics alter the activity of DNA interacting enzymes used as targets for cancer treatment, such as DNA topoisomerase I, and they are cytotoxic only in the presence of a transfection agent. The aim of our study was to improve internalization and selective delivery of these highly charged molecules to cancer cells. For this purpose, we synthesized an antibody-drug conjugate (ADC) using a DNA mimic as a payload to specifically target cancer cells overexpressing HER2. We report the bioconjugation of a 16-mer DNA mimic with trastuzumab and its functional validation in breast and ovarian cancer cells expressing various levels of HER2. Binding of the ADC to HER2 increased with the expression of the receptor. The ADC was internalized into cells and was more efficient than trastuzumab at inhibiting their growth in vitro. These results provide proof of concept that it is possible to site-specifically graft high molecular weight payloads such as DNA mimics onto monoclonal antibodies to improve their selective internalization and delivery in cancer cells.

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Platinum Complexes in Colorectal Cancer and Other Solid Tumors

Cancers ◽

10.3390/cancers13092073 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2073

Author(s):

Beate Köberle ◽

Sarah Schoch

Keyword(s):

Colorectal Cancer ◽

Dna Damage ◽

Dna Repair ◽

Cancer Cells ◽

Cisplatin Resistance ◽

Platinum Complexes ◽

Dna Lesions ◽

Dna Damage Signaling ◽

Repair Mechanisms ◽

P53 Inactivation

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.

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Tunable and Photoswitchable Chemically Induced Dimerization for Chemo-optogenetic Control of Protein and Organelle Positioning

Angewandte Chemie ◽

10.1002/ange.201800140 ◽

2018 ◽

Vol 130 (23) ◽

pp. 6912-6915 ◽

Cited By ~ 4

Author(s):

Xi Chen ◽

Yao-Wen Wu

Keyword(s):

Chemically Induced ◽

Chemically Induced Dimerization ◽

Optogenetic Control

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MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1903150116 ◽

2019 ◽

Vol 116 (35) ◽

pp. 17438-17443 ◽

Cited By ~ 6

Author(s):

Gayathri Srinivasan ◽

Elizabeth A. Williamson ◽

Kimi Kong ◽

Aruna S. Jaiswal ◽

Guangcun Huang ◽

...

Keyword(s):

Dna Repair ◽

Cancer Cells ◽

Synthetic Lethality ◽

Negative Regulator ◽

Nonhomologous End Joining ◽

Chromosomal Translocations ◽

Replication Forks ◽

Repair Pathway ◽

End Joining ◽

Parp1 Inhibitors

Defects in DNA repair give rise to genomic instability, leading to neoplasia. Cancer cells defective in one DNA repair pathway can become reliant on remaining repair pathways for survival and proliferation. This attribute of cancer cells can be exploited therapeutically, by inhibiting the remaining repair pathway, a process termed synthetic lethality. This process underlies the mechanism of the Poly-ADP ribose polymerase-1 (PARP1) inhibitors in clinical use, which target BRCA1 deficient cancers, which is indispensable for homologous recombination (HR) DNA repair. HR is the major repair pathway for stressed replication forks, but when BRCA1 is deficient, stressed forks are repaired by back-up pathways such as alternative nonhomologous end-joining (aNHEJ). Unlike HR, aNHEJ is nonconservative, and can mediate chromosomal translocations. In this study we have found that miR223-3p decreases expression of PARP1, CtIP, and Pso4, each of which are aNHEJ components. In most cells, high levels of microRNA (miR) 223–3p repress aNHEJ, decreasing the risk of chromosomal translocations. Deletion of the miR223 locus in mice increases PARP1 levels in hematopoietic cells and enhances their risk of unprovoked chromosomal translocations. We also discovered that cancer cells deficient in BRCA1 or its obligate partner BRCA1-Associated Protein-1 (BAP1) routinely repress miR223-3p to permit repair of stressed replication forks via aNHEJ. Reconstituting the expression of miR223-3p in BRCA1- and BAP1-deficient cancer cells results in reduced repair of stressed replication forks and synthetic lethality. Thus, miR223-3p is a negative regulator of the aNHEJ DNA repair and represents a therapeutic pathway for BRCA1- or BAP1-deficient cancers.

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