Selective pericentromeric heterochromatin dismantling caused by TP53 activation during senescence

Abstract Cellular senescence triggers various types of heterochromatin remodelling that contribute to aging. However the age-ralated mechanisms that lead to these epigenetic alterations remain elusive. Here, we asked how two key aging hallmarks, telomere shortening and consititutive heterochromatin loss, are mechanistically connected during senescence. We show that, at the onset of senescence, pericentromeric heterochromatin is specifically dismantled consisting of chromatin decondensation, accumulation of DNA breakages, illegitimate recombination and loss of DNA. This process is caused by telomere shortening or genotoxic stress by a sequence of events starting from p53-dependent downregulation of the telomere protective protein TRF2. The resulting loss of TRF2 at pericentromeres trigger DNA breaks activating ATM, which in turn leads to heterochromatin decondensation by releasing Kap1 and Lamin B1, recombination and satellite DNA excision found in the cytosol associated to cGAS. This TP53-TRF2 axis activates the interferon response and the formation of chromosome rearrangements when the cells escape the senescent growth arrest. Overall, these results reveal the role of p53 as pericentromeric disassembler and define the basic principles of how a TP53-dependent senescence inducer hierarchically leadns to selective pericentromeric dismantling through the downregulation of TRF2.

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MRG15-mediated tethering of PALB2 to unperturbed chromatin protects active genes from genotoxic stress

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1620208114 ◽

2017 ◽

Vol 114 (29) ◽

pp. 7671-7676 ◽

Cited By ~ 23

Author(s):

Jean-Yves Bleuyard ◽

Marjorie Fournier ◽

Ryuichiro Nakato ◽

Anthony M. Couturier ◽

Yuki Katou ◽

...

Keyword(s):

Dna Replication ◽

Genome Stability ◽

Genome Instability ◽

Genotoxic Stress ◽

Missense Mutations ◽

Dna Breaks ◽

Metaphase Chromosomes ◽

Repair Factor ◽

Active Genes

The partner and localiser of BRCA2 (PALB2) plays important roles in the maintenance of genome integrity and protection against cancer. Although PALB2 is commonly described as a repair factor recruited to sites of DNA breaks, recent studies provide evidence that PALB2 also associates with unperturbed chromatin. Here, we investigated the previously poorly described role of chromatin-associated PALB2 in undamaged cells. We found that PALB2 associates with active genes through its major binding partner, MRG15, which recognizes histone H3 trimethylated at lysine 36 (H3K36me3) by the SETD2 methyltransferase. Missense mutations that ablate PALB2 binding to MRG15 confer elevated sensitivity to the topoisomerase inhibitor camptothecin (CPT) and increased levels of aberrant metaphase chromosomes and DNA stress in gene bodies, which were suppressed by preventing DNA replication. Remarkably, the level of PALB2 at genic regions was frequently decreased, rather than increased, upon CPT treatment. We propose that the steady-state presence of PALB2 at active genes, mediated through the SETD2/H3K36me3/MRG15 axis, ensures an immediate response to DNA stress and therefore effective protection of these regions during DNA replication. This study provides a conceptual advance in demonstrating that the constitutive chromatin association of repair factors plays a key role in the maintenance of genome stability and furthers our understanding of why PALB2 defects lead to human genome instability syndromes.

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The Emerging Role of HP1 in the DNA Damage Response

Molecular and Cellular Biology ◽

10.1128/mcb.01048-09 ◽

2009 ◽

Vol 29 (24) ◽

pp. 6335-6340 ◽

Cited By ~ 84

Author(s):

Christoffel Dinant ◽

Martijn S. Luijsterburg

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Dna Damage Response ◽

Genotoxic Stress ◽

Active Role ◽

Dna Breaks ◽

Heterochromatin Protein 1 ◽

Damage Response ◽

Hp1 Proteins

ABSTRACT Heterochromatin protein 1 (HP1) family members are versatile proteins involved in transcription, chromatin organization, and replication. Recent findings now have implicated HP1 proteins in the DNA damage response as well. Cell-biological approaches showed that reducing the levels of all three HP1 isoforms enhances DNA repair, possibly due to heterochromatin relaxation. Additionally, HP1 is phosphorylated in response to DNA damage, which was suggested to initiate the DNA damage response. These findings have led to the conclusion that heterochromatic proteins are inhibitory to repair and that their dissociation from heterochromatin may facilitate repair. In contrast with an inhibitory role, a more active role for HP1 in DNA repair also was proposed based on the finding that all HP1 isoforms are recruited to UV-induced lesions, oxidative lesions, and DNA breaks. The loss of HP1 renders nematodes highly sensitive to DNA damage, and mice lacking HP1β suffer from genomic instability, suggesting that the loss of HP1 is not necessarily beneficial for repair. These findings raise the possibility that HP1 facilitates DNA repair by reorganizing chromatin, which may involve interactions between phosphorylated HP1 and other DNA damage response proteins. Taken together, these studies illustrate an emerging role of HP1 proteins in the response to genotoxic stress.

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Nuclear sensing of mitochondrial DNA breaks enhances immune surveillance

10.1101/2020.01.31.929075 ◽

2020 ◽

Cited By ~ 3

Author(s):

Marco Tigano ◽

Danielle C. Vargas ◽

Yi Fu ◽

Samuel Tremblay-Belzile ◽

Agnel Sfeir

Keyword(s):

Nuclear Dna ◽

Immune Surveillance ◽

Independent Set ◽

Genotoxic Stress ◽

Interferon Response ◽

Mitochondrial Rna ◽

Type I ◽

Dna Breaks ◽

Interferon Stimulated Genes ◽

Surveillance Mechanism

Mitochondrial double-strand breaks (mtDSBs) are toxic lesions that compromise mitochondrial function. Mito-nuclear communication is essential to maintain cellular homeostasis, however, the nuclear response to mtDSBs remains unknown. Using mitochondrial-targeted TALENs, we show that mtDSBs activate a type I interferon response evidenced by phosphorylation of STAT1 and activation of interferon stimulated genes (ISG). Following mtDNA break formation, BAK-BAX mediated herniation releases mitochondrial RNA to the cytoplasm and trigger a RIG-I/MAVS-dependent immune response. In an independent set of experiments, we investigate the role of mtDSBs in interferon signaling due to genotoxic stress. Our data reveal that activation of ISGs is greatly diminished when cells lacking mtDNA are exposed to ionizing radiation. Furthermore, we show that mtDNA breaks synergize with nuclear DNA damage to mount a robust interferon response. In conclusion, cytoplasmic accumulation of mitochondrial RNA is as an intrinsic immune surveillance mechanism for cells to cope with mtDSBs, including ones inflicted by genotoxic agents.

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Quantum postulate vs. quantum nonlocality: on the role of the Planck constant in Bell’s argument

Foundations of Physics ◽

10.1007/s10701-021-00430-3 ◽

2021 ◽

Vol 51 (1) ◽

Author(s):

Andrei Khrennikov

Keyword(s):

Quantum Nonlocality ◽

Quantum Mechanical ◽

Quantum Foundations ◽

Planck Constant ◽

Variable Model ◽

Basic Principles ◽

Fundamental Feature ◽

Hidden Variable ◽

Bell Model

AbstractWe present a quantum mechanical (QM) analysis of Bell’s approach to quantum foundations based on his hidden-variable model. We claim and try to justify that the Bell model contradicts to the Heinsenberg’s uncertainty and Bohr’s complementarity principles. The aim of this note is to point to the physical seed of the aforementioned principles. This is the Bohr’s quantum postulate: the existence of indivisible quantum of action given by the Planck constant h. By contradicting these basic principles of QM, Bell’s model implies rejection of this postulate as well. Thus, this hidden-variable model contradicts not only the QM-formalism, but also the fundamental feature of the quantum world discovered by Planck.

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Multifunctional Role of Astrocyte Elevated Gene-1 (AEG-1) in Cancer: Focus on Drug Resistance

Cancers ◽

10.3390/cancers13081792 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1792

Author(s):

Debashri Manna ◽

Devanand Sarkar

Keyword(s):

Drug Resistance ◽

Cancer Cells ◽

Cancer Development ◽

Epigenetic Alterations ◽

Hallmarks Of Cancer ◽

Comprehensive Description ◽

Molecular Abnormalities ◽

Selective Pressures ◽

Resistance To Chemotherapy

Cancer development results from the acquisition of numerous genetic and epigenetic alterations in cancer cells themselves, as well as continuous changes in their microenvironment. The plasticity of cancer cells allows them to continuously adapt to selective pressures brought forth by exogenous environmental stresses, the internal milieu of the tumor and cancer treatment itself. Resistance to treatment, either inherent or acquired after the commencement of treatment, is a major obstacle an oncologist confronts in an endeavor to efficiently manage the disease. Resistance to chemotherapy, chemoresistance, is an important hallmark of aggressive cancers, and driver oncogene-induced signaling pathways and molecular abnormalities create the platform for chemoresistance. The oncogene Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) is overexpressed in a diverse array of cancers, and its overexpression promotes all the hallmarks of cancer, such as proliferation, invasion, metastasis, angiogenesis and chemoresistance. The present review provides a comprehensive description of the molecular mechanism by which AEG-1 promotes tumorigenesis, with a special emphasis on its ability to regulate chemoresistance.

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Modulatory role of tea in arsenic induced epigenetic alterations in carcinogenesis

The Nucleus ◽

10.1007/s13237-020-00346-9 ◽

2021 ◽

Author(s):

Archismaan Ghosh ◽

Sutapa Mukherjee ◽

Madhumita Roy ◽

Amitava Datta

Keyword(s):

Epigenetic Alterations

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Lamin B1 promotes tumor progression and metastasis in primary prostate cancer patients

Future Oncology ◽

10.2217/fon-2020-0825 ◽

2020 ◽

Author(s):

Fei Luo ◽

Jiaxi Han ◽

Yatong Chen ◽

Kuo Yang ◽

Zhihua Zhang ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Progression ◽

Cancer Metastasis ◽

Disease Free Survival ◽

Free Survival ◽

Lamin B1 ◽

Kaplan Meier ◽

Primary Prostate Cancer ◽

Clinical Relationship

Aims: To determine the role of lamin B1 (LMNB1) in the progression and metastasis of primary prostate cancer (PC). Patients & methods: Two PC cohorts were used to investigate the clinical relationship between LMNB1 expression and tumor progression and metastasis. Results: The qRT-PCR results revealed that LMNB1 expression was markedly increased in patients with aggressive features and was associated with worse prognosis. Logistic regression analyses indicated that LMNB1 expression is an independent risk factor for distant metastasis. Kaplan–Meier analysis showed that increased LMNB1 levels were related to poor disease-free survival in the primary PC cohort. Conclusion: This study reveals that upregulation of LMNB1 is associated with cancer metastasis and poor survival outcomes in primary PC patients.

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COVID-19 Shuts Doors to Flu but Keeps Them Open to Rhinoviruses

Biology ◽

10.3390/biology10080733 ◽

2021 ◽

Vol 10 (8) ◽

pp. 733

Author(s):

Irina Kiseleva ◽

Andrey Ksenafontov

Keyword(s):

Influenza Pandemic ◽

Age Groups ◽

Influenza Viruses ◽

Interferon Response ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Mild Disease ◽

Viral Interference ◽

The Common

It is well known that rhinoviruses are distributed across the globe and are the most common cause of the common cold in all age groups. Rhinoviruses are widely considered to be harmless because they are generally perceived as respiratory viruses only capable of causing mild disease. However, they may also infect the lower respiratory tract, inducing chronic obstructive pulmonary disease and exacerbations of asthma, bronchiolitis, etc. The role of rhinoviruses in pathogenesis and the epidemiological process is underestimated, and they need to be intensively studied. In the light of recent data, it is now known that rhinoviruses could be one of the key epidemiological barriers that may influence the spread of influenza and novel coronaviruses. It has been reported that endemic human rhinoviruses delayed the development of the H1N1pdm09 influenza pandemic through viral interference. Moreover, human rhinoviruses have been suggested to block SARS-CoV-2 replication in the airways by triggering an interferon response. In this review, we summarized the main biological characteristics of genetically distinct viruses such as rhinoviruses, influenza viruses, and SARS-CoV-2 in an attempt to illuminate their main discrepancies and similarities. We hope that this comparative analysis will help us to better understand in which direction research in this area should move.

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What Is the Metabolic Amplification of Insulin Secretion and Is It (Still) Relevant?

Metabolites ◽

10.3390/metabo11060355 ◽

2021 ◽

Vol 11 (6) ◽

pp. 355

Author(s):

Ingo Rustenbeck ◽

Torben Schulze ◽

Mai Morsi ◽

Mohammed Alshafei ◽

Uwe Panten

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Adenine Nucleotides ◽

Pancreatic Beta Cell ◽

Secretory Response ◽

Mitochondrial Activity ◽

Insulin Synthesis ◽

Sequence Of Events ◽

Insulin Granules

The pancreatic beta-cell transduces the availability of nutrients into the secretion of insulin. While this process is extensively modified by hormones and neurotransmitters, it is the availability of nutrients, above all glucose, which sets the process of insulin synthesis and secretion in motion. The central role of the mitochondria in this process was identified decades ago, but how changes in mitochondrial activity are coupled to the exocytosis of insulin granules is still incompletely understood. The identification of ATP-sensitive K+-channels provided the link between the level of adenine nucleotides and the electrical activity of the beta cell, but the depolarization-induced Ca2+-influx into the beta cells, although necessary for stimulated secretion, is not sufficient to generate the secretion pattern as produced by glucose and other nutrient secretagogues. The metabolic amplification of insulin secretion is thus the sequence of events that enables the secretory response to a nutrient secretagogue to exceed the secretory response to a purely depolarizing stimulus and is thus of prime importance. Since the cataplerotic export of mitochondrial metabolites is involved in this signaling, an orienting overview on the topic of nutrient secretagogues beyond glucose is included. Their judicious use may help to define better the nature of the signals and their mechanism of action.

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Peripheral muscarinic control of norepinephrine release in the cardiovascular system

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1980.239.6.h713 ◽

1980 ◽

Vol 239 (6) ◽

pp. H713-H720 ◽

Cited By ~ 5

Author(s):

E. Muscholl

Keyword(s):

Physiological Role ◽

Sympathetic Nerves ◽

Adrenergic Nerve ◽

Sequence Of Events ◽

Adrenergic Response ◽

Adrenergic Nerve Terminals ◽

Muscarinic Cholinergic ◽

Related Compounds ◽

Stimulation Of

Activation of muscarinic cholinergic receptors located at the terminal adrenergic nerve fiber inhibits the process of exocytotic norepinephrine (NE) release. This neuromodulatory effect of acetylcholine and related compounds has been discovered as a pharmacological phenomenon. Subsequently, evidence for a physiological role of the presynaptic muscarinic inhibition was obtained on organs known to be innervated by the autonomic ground plexus (Hillarp, Acta. Physiol. Scand. 46, Suppl. 157: 1-68, 1959) in which terminal adrenergic and cholinergic axons run side by side. Thus, in the heart electrical vagal stimulation inhibits the release of NE evoked by stimulation of sympathetic nerves, and this is reflected by a corresponding decrease in the postsynaptic adrenergic response. On the other hand, muscarinic antagonists such as atropine enhance the NE release evoked by field stimulation of tissues innervated by the autonomic ground plexus. The presynaptic muscarine receptor of adrenergic nerve terminals probably restricts the influx of calcium ions that triggers the release of NE. However, the sequence of events between recognition of the muscarinic compound by the receptor and the process of exocytosis still remains to be clarified.

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