Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation

The dynamic nature of the nuclear envelope (NE) is often underestimated. The NE protects, regulates, and organizes the eukaryote genome and adapts to epigenetic changes and to its environment. The NE morphology is characterized by a wide range of diversity and abnormality such as invagination and blebbing, and it is a diagnostic factor for pathologies such as cancer. Recently, the micronuclei, a small nucleus that contains a full chromosome or a fragment thereof, has gained much attention. The NE of micronuclei is prone to collapse, leading to DNA release into the cytoplasm with consequences ranging from the activation of the cGAS/STING pathway, an innate immune response, to the creation of chromosomal instability. The discovery of those mechanisms has revolutionized the understanding of some inflammation-related diseases and the origin of complex chromosomal rearrangements, as observed during the initiation of tumorigenesis. Herein, we will highlight the complexity of the NE biology and discuss the clinical symptoms observed in NE-related diseases. The interplay between innate immunity, genomic instability, and nuclear envelope leakage could be a major focus in future years to explain a wide range of diseases and could lead to new classes of therapeutics.

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Loss of CBX2 induces genome instability and senescence-associated chromosomal rearrangements

The Journal of Cell Biology ◽

10.1083/jcb.201910149 ◽

2020 ◽

Vol 219 (11) ◽

Author(s):

Claudia Baumann ◽

Xiangyu Zhang ◽

Rabindranath De La Fuente

Keyword(s):

Dna Sequences ◽

Genome Stability ◽

Large Scale ◽

Genome Instability ◽

Chromosomal Rearrangements ◽

Chromosome Instability ◽

Nuclear Architecture ◽

Polycomb Group ◽

Polycomb Group Protein ◽

Wide Range

The polycomb group protein CBX2 is an important epigenetic reader involved in cell proliferation and differentiation. While CBX2 overexpression occurs in a wide range of human tumors, targeted deletion results in homeotic transformation, proliferative defects, and premature senescence. However, its cellular function(s) and whether it plays a role in maintenance of genome stability remain to be determined. Here, we demonstrate that loss of CBX2 in mouse fibroblasts induces abnormal large-scale chromatin structure and chromosome instability. Integrative transcriptome analysis and ATAC-seq revealed a significant dysregulation of transcripts involved in DNA repair, chromocenter formation, and tumorigenesis in addition to changes in chromatin accessibility of genes involved in lateral sclerosis, basal transcription factors, and folate metabolism. Notably, Cbx2−/− cells exhibit prominent decondensation of satellite DNA sequences at metaphase and increased sister chromatid recombination events leading to rampant chromosome instability. The presence of extensive centromere and telomere defects suggests a prominent role for CBX2 in heterochromatin homeostasis and the regulation of nuclear architecture.

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Faculty Opinions recommendation of Translesion Polymerases Drive Microhomology-Mediated Break-Induced Replication Leading to Complex Chromosomal Rearrangements.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726014549.793513001 ◽

2016 ◽

Author(s):

Antony Carr

Keyword(s):

Chromosomal Rearrangements ◽

Complex Chromosomal Rearrangements ◽

Translesion Polymerases ◽

Break Induced Replication

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Cerebellotrigeminal Dermal Dysplasia (Gómez-López-Hernández Syndrome)

Journal of Pediatric Neurology ◽

10.1055/s-0038-1667021 ◽

2018 ◽

Vol 16 (05) ◽

pp. 362-368 ◽

Cited By ~ 1

Author(s):

Federica Sullo ◽

Agata Polizzi ◽

Stefano Catanzaro ◽

Selene Mantegna ◽

Francesco Lacarrubba ◽

...

Keyword(s):

De Novo ◽

Chromosomal Rearrangements ◽

Number Of Patients ◽

Wide Range ◽

Visual Problems ◽

Neurodevelopmental Abnormalities ◽

Clinical Triad ◽

High Degree ◽

Motor Handicap

Cerebellotrigeminal dermal (CTD) dysplasia is a rare neurocutaneous disorder characterized by a triad of symptoms: bilateral parieto-occipital alopecia, facial anesthesia in the trigeminal area, and rhombencephalosynapsis (RES), confirmed by cranial magnetic resonance imaging. CTD dysplasia is also known as Gómez-López-Hernández syndrome. So far, only 35 cases have been described with varying symptomatology. The etiology remains unknown. Either spontaneous dominant mutations or de novo chromosomal rearrangements have been proposed as possible explanations. In addition to its clinical triad of RES, parietal alopecia, and trigeminal anesthesia, CTD dysplasia is associated with a wide range of phenotypic and neurodevelopmental abnormalities.Treatment is symptomatic and includes physical rehabilitation, special education, dental care, and ocular protection against self-induced corneal trauma that causes ulcers and, later, corneal opacification. The prognosis is correlated to the mental development, motor handicap, corneal–facial anesthesia, and visual problems. Follow-up on a large number of patients with CTD dysplasia has never been reported and experience is limited to few cases to date. High degree of suspicion in a child presenting with characteristic alopecia and RES has a great importance in diagnosis of this syndrome.

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Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

Cancers ◽

10.3390/cancers13030396 ◽

2021 ◽

Vol 13 (3) ◽

pp. 396

Author(s):

Timon A. Bloedjes ◽

Guus de Wilde ◽

Jeroen E. J. Guikema

Keyword(s):

Multiple Myeloma ◽

Cell Metabolism ◽

Chromosomal Rearrangements ◽

Chromosomal Translocations ◽

Metabolic Effects ◽

Aberrant Expression ◽

Metabolic Functions ◽

Complex Chromosomal Rearrangements ◽

Cancer Cell Metabolism ◽

The Many

Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. Multiple myeloma (MM) is a genetically heterogeneous disease that arises from terminally differentiated B cells. MM is characterized by reciprocal chromosomal translocations that often involve the immunoglobulin loci and a restricted set of partner loci, and complex chromosomal rearrangements that are associated with disease progression. Recurrent chromosomal aberrations in MM result in the aberrant expression of MYC, cyclin D1, FGFR3/MMSET and MAF/MAFB. In recent years, the intricate mechanisms that drive cancer cell metabolism and the many metabolic functions of the aforementioned MM-associated oncogenes have been investigated. Here, we discuss the metabolic consequences of recurrent chromosomal translocations in MM and provide a framework for the identification of metabolic changes that characterize MM cells.

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Prodromal Dementia With Lewy Bodies: Evolution of Symptoms and Predictors of Dementia Onset

Journal of Geriatric Psychiatry and Neurology ◽

10.1177/08919887211023586 ◽

2021 ◽

pp. 089198872110235

Author(s):

Kathryn A. Wyman-Chick ◽

Lauren R. O’Keefe ◽

Daniel Weintraub ◽

Melissa J. Armstrong ◽

Michael Rosenbloom ◽

...

Keyword(s):

Clinical Features ◽

Dementia With Lewy Bodies ◽

Clinical Symptoms ◽

Neuropsychiatric Symptoms ◽

Lewy Bodies ◽

Rem Sleep Behavior Disorder ◽

Data Set ◽

Wide Range ◽

Prodromal Dementia ◽

Dementia Onset

Background: Research criteria for prodromal dementia with Lewy bodies (DLB) were published in 2020, but little is known regarding prodromal DLB in clinical settings. Methods: We identified non-demented participants without neurodegenerative disease from the National Alzheimer’s Coordinating Center Uniform Data Set who converted to DLB at a subsequent visit. Prevalence of neuropsychiatric and motor symptoms were examined up to 5 years prior to DLB diagnosis. Results: The sample included 116 participants clinically diagnosed with DLB and 348 age and sex-matched (1:3) Healthy Controls. Motor slowing was present in approximately 70% of participants 3 years prior to DLB diagnosis. In the prodromal phase, 50% of DLB participants demonstrated gait disorder, 70% had rigidity, 20% endorsed visual hallucinations, and over 50% of participants endorsed REM sleep behavior disorder. Apathy, depression, and anxiety were common prodromal neuropsychiatric symptoms. The presence of 1+ core clinical features of DLB in combination with apathy, depression, or anxiety resulted in the greatest AUC (0.815; 95% CI: 0.767, 0.865) for distinguishing HC from prodromal DLB 1 year prior to diagnosis. The presence of 2+ core clinical features was also accurate in differentiating between groups (AUC = 0.806; 95% CI: 0.756, 0.855). Conclusion: A wide range of motor, neuropsychiatric and other core clinical symptoms are common in prodromal DLB. A combination of core clinical features, neuropsychiatric symptoms and cognitive impairment can accurately differentiate DLB from normal aging prior to dementia onset.

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OASIS/CREB3L1 is a factor that responds to nuclear envelope stress

Cell Death Discovery ◽

10.1038/s41420-021-00540-x ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yasunao Kamikawa ◽

Atsushi Saito ◽

Koji Matsuhisa ◽

Masayuki Kaneko ◽

Rie Asada ◽

...

Keyword(s):

Cell Cycle ◽

Endoplasmic Reticulum ◽

Nuclear Envelope ◽

Genome Instability ◽

Nuclear Lamina ◽

Nuclear Deformation ◽

Membrane Domain ◽

Stress Response Pathway ◽

Envelope Stress ◽

Genome Activity

AbstractThe nuclear envelope (NE) safeguards the genome and is pivotal for regulating genome activity as the structural scaffold of higher-order chromatin organization. NE had been thought as the stable during the interphase of cell cycle. However, recent studies have revealed that the NE can be damaged by various stresses such as mechanical stress and cellular senescence. These types of stresses are called NE stress. It has been proposed that NE stress is closely related to cellular dysfunctions such as genome instability and cell death. Here, we found that an endoplasmic reticulum (ER)-resident transmembrane transcription factor, OASIS, accumulates at damaged NE. Notably, the major components of nuclear lamina, Lamin proteins were depleted at the NE where OASIS accumulates. We previously demonstrated that OASIS is cleaved at the membrane domain in response to ER stress. In contrast, OASIS accumulates as the full-length form to damaged NE in response to NE stress. The accumulation to damaged NE is specific for OASIS among OASIS family members. Intriguingly, OASIS colocalizes with the components of linker of nucleoskeleton and cytoskeleton complexes, SUN2 and Nesprin-2 at the damaged NE. OASIS partially colocalizes with BAF, LEM domain proteins, and a component of ESCRT III, which are involved in the repair of ruptured NE. Furthermore, OASIS suppresses DNA damage induced by NE stress and restores nuclear deformation under NE stress conditions. Our findings reveal a novel NE stress response pathway mediated by OASIS.

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Role of Insulin in Health and Disease: An Update

International Journal of Molecular Sciences ◽

10.3390/ijms22126403 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6403

Author(s):

Md Saidur Rahman ◽

Khandkar Shaharina Hossain ◽

Sharnali Das ◽

Sushmita Kundu ◽

Elikanah Olusayo Adegoke ◽

...

Keyword(s):

Insulin Signaling ◽

Basic Research ◽

Future Research ◽

Protective Effects ◽

Glucose Levels ◽

Physiological Processes ◽

Blood Glucose Levels ◽

Wide Range ◽

Health And Disease

Insulin is a polypeptide hormone mainly secreted by β cells in the islets of Langerhans of the pancreas. The hormone potentially coordinates with glucagon to modulate blood glucose levels; insulin acts via an anabolic pathway, while glucagon performs catabolic functions. Insulin regulates glucose levels in the bloodstream and induces glucose storage in the liver, muscles, and adipose tissue, resulting in overall weight gain. The modulation of a wide range of physiological processes by insulin makes its synthesis and levels critical in the onset and progression of several chronic diseases. Although clinical and basic research has made significant progress in understanding the role of insulin in several pathophysiological processes, many aspects of these functions have yet to be elucidated. This review provides an update on insulin secretion and regulation, and its physiological roles and functions in different organs and cells, and implications to overall health. We cast light on recent advances in insulin-signaling targeted therapies, the protective effects of insulin signaling activators against disease, and recommendations and directions for future research.

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Rtn1p Is Involved in Structuring the Cortical Endoplasmic Reticulum

Molecular Biology of the Cell ◽

10.1091/mbc.e06-01-0080 ◽

2006 ◽

Vol 17 (7) ◽

pp. 3009-3020 ◽

Cited By ~ 90

Author(s):

Johan-Owen De Craene ◽

Jeff Coleman ◽

Paula Estrada de Martin ◽

Marc Pypaert ◽

Scott Anderson ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Nuclear Envelope ◽

Fluorescent Protein ◽

Cell Cortex ◽

Proteomic Screen ◽

Wide Range ◽

Membrane Spanning ◽

Green Fluorescent ◽

Hydrophilic Loop ◽

Yeast Mutants

The endoplasmic reticulum (ER) contains both cisternal and reticular elements in one contiguous structure. We identified rtn1Δ in a systematic screen for yeast mutants with altered ER morphology. The ER in rtn1Δ cells is predominantly cisternal rather than reticular, yet the net surface area of ER is not significantly changed. Rtn1-green fluorescent protein (GFP) associates with the reticular ER at the cell cortex and with the tubules that connect the cortical ER to the nuclear envelope, but not with the nuclear envelope itself. Rtn1p overexpression also results in an altered ER structure. Rtn proteins are found on the ER in a wide range of eukaryotes and are defined by two membrane-spanning domains flanking a conserved hydrophilic loop. Our results suggest that Rtn proteins may direct the formation of reticulated ER. We independently identified Rtn1p in a proteomic screen for proteins associated with the exocyst vesicle tethering complex. The conserved hydophilic loop of Rtn1p binds to the exocyst subunit Sec6p. Overexpression of this loop results in a modest accumulation of secretory vesicles, suggesting impaired exocyst function. The interaction of Rtn1p with the exocyst at the bud tip may trigger the formation of a cortical ER network in yeast buds.

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