Genomic instability and DNA replication defects in progeroid syndromes

Burla, Romina; Torre, Mattia La; Merigliano, Chiara; Vernı̀, Fiammetta; Saggio, Isabella

doi:10.1080/19491034.2018.1476793

Cited by 51 publications

(53 citation statements)

References 116 publications

(95 reference statements)

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“…To determine whether the accumulation of DNA damage during in vitro differentiation of Lmna KO myoblasts was caused by progressive new nuclear damage or defects in DNA damage repair, which had been reported in several progeroid laminopathies [40][41][42] , we subjected Lmna KO and wild-type myofibers to a pulse of gamma irradiation and monitored γH2AX levels at 3, 6, and 24 hours post-treatment. Consistent with previous studies 43 , irradiation resulted in a rapid increase in the number of γH2AX foci at 3 hours that then gradually resolved and returned to baseline by 24 hours post irradiation (Suppl.…”

Section: Lmna Ko Myonuclei Have Increased Levels Of Dna Damage In Vitmentioning

confidence: 99%

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Earle

Kirby

Fedorchak

et al. 2018

Preprint

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Mutations in the human LMNA gene, which encodes the nuclear envelope proteins lamins A and C, cause autosomal dominant Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, limb-girdle muscular dystrophy, and other diseases collectively known as laminopathies. The molecular mechanisms responsible for these diseases remain incompletely understood, but the muscle-specific defects suggest that mutations may render nuclei more susceptible to mechanical stress. Using three mouse models of muscle laminopathies, we found that Lmna mutations caused extensive nuclear envelope damage, consisting of chromatin protrusions and transient rupture of the nuclear envelope, in skeletal muscle cells in vitro and in vivo. The nuclear envelope damage was associated with progressive DNA damage, activation of DNA damage response pathways, and reduced viability. Intriguingly, nuclear envelope damage resulted from nuclear movement in maturing skeletal muscle cells, rather than actomyosin contractility, and was reversed by either depletion of kinesin-1 or stabilization of microtubules. Depletion of kinesin-1 also rescued DNA damage, indicating that DNA damage is the result of nuclear envelope damage. The extent of nuclear envelope damage and DNA damage in the different Lmna mouse models strongly correlated with the disease onset and severity in vivo, and inducing DNA damage in wild-type muscle cells was sufficient to phenocopy the reduced cell viability of lamin A/C-deficient muscle cells, suggesting a causative role of DNA damage in disease pathogenesis. Corroborating the mouse model data, muscle biopsies from patients with LMNA associated muscular dystrophy similarly revealed significant DNA damage compared to age-matched controls, particularly in severe cases of the disease. Taken together, these findings point to a new and important role of DNA damage as a pathogenic contributor for these skeletal muscle diseases.

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Section: Lmna Ko Myonuclei Have Increased Levels Of Dna Damage In Vitmentioning

confidence: 99%

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Earle

Kirby

Fedorchak

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…In order to identify the central processes secondary to these modifications, the coexpression networks analysis was performed. 251 (56 %) of the 442 deg had a coexpression level higher than the level to be expected randomly, hence, almost half of the deg presented expression patterns with low correlation to other deg, this, again, can be explained by the heterogeneity of aging and by the stochastic nature of some processes associated with it, such as the accumulation of dna mutations over the years that would produce expression patterns not consistent among different samples, for the pfc of each person will have its own random mutation accumulation history (31,32).…”

Section: Co-expression Network Analysis Identifies Possible Hub Genesmentioning

confidence: 99%

Co-Expression Network Analysis Identifies Possible Hub Genes in Aging of the Human Prefrontal Cortex

et al. 2019

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Introducción: el envejecimiento es el principal factor de riesgo para el desarrollo de enfermedades crónicas como el cáncer, la diabetes, el Parkinson y el Alzheimer. El sistema nervioso central es particularmente susceptible al deterioro funcional progresivo asociado con la edad, entre las regiones cerebrales con mayor compromiso se encuentra la corteza prefrontal (CPF). Estudios de transcriptómica de esta región han identificado como características fundamentales del proceso de envejecimiento la disminución de la función sináptica y la activación de las células de la neuroglia. No es claro cuáles son las causas iniciales, ni los mecanismos moleculares subyacentes a estas alteraciones. El objetivo de este estudio fue identificar genes clave en la desregulación transcriptómica en el envejecimiento de la CPF para avanzar en el conocimiento de este proceso. Materiales y métodos: se hizo un análisis de coexpresión de genes de los transcriptomas de 45 personas entre 60 y 80 años con el de 38 personas entre 20 y 40 años. Las redes fueron visualizadas y analizadas usando Cytoscape, se usó citoHubba para determinar qué genes tenían las mejores características topológicas en las redes de coexpresión. Resultados: se identificaron cinco genes con características topológicas altas. Cuatro de ellos —hpca, cacng3, ca10, plppr4— reprimidos y uno sobreexpresado —Cryab—. Conclusión: los cuatro genes reprimidos se expresan preferencialmente en neuronas y regulan la función sináptica y la plasticidad neuronal, mientras el gen sobreexpresado es típico de células de la glía y se expresa como respuesta a daño neuronal facilitando la mielinización y la regeneración neuronal.

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“…Установлено, что прогерия, или синдром Гетчинсона-Гилфорда, возникающая вследствие мутаций гена LMNA, кодирующего ламин А (ламины -белки, из которых строится особый слой оболочки клеточного ядра), связана с геномной нестабильностью, уменьшением длины теломер и нарушением развития стволовых клеток. Эти данные привели к гипотезе, согласно которой при прогерии развивается ряд патологических изменений, которые управляют обычным процессом старения [35].…”

Section: обзоры литературыunclassified

Biomarkers of early cardiovascular aging

Грознова¹,

Миклашевич²,

Воинова³

et al. 2019

Ross. vestn. perinatol. pediatr.

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Genetic aspects regulate the intensity and rate of aging (no toxic effects considered), their negative role depends on the pathogenicity of the mutation. The light variant of the genetic “defect” has no clinical signs which feature a certain known genetic syndrome, but it has the biochemical, immunological, vascular and other abnormalities leading to pathological aging. In the most severe case, e.g. progeria, pathological aging is the main phenotypic symptom that manifests already in childhood. The subject of the pathological aging research covers the whole range of intermediate states. The review focuses on aging in individuals without validated signs of disease: coronary heart disease, hypertension, diabetes or fasting hyperglycemia, hyperlipidemia, and others. The authors present the main searching directions of aging biomarkers (size and speed of telomere shortening, breaks in their terminal loops; expression of inflammatory proteins, synaptic interactions proteins and neurotrophic processes; mitochondrial biogenesis; endothelial dysfunction; DNA methylation activity).

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Genomic instability and DNA replication defects in progeroid syndromes

Cited by 51 publications

References 116 publications

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Co-Expression Network Analysis Identifies Possible Hub Genes in Aging of the Human Prefrontal Cortex

Biomarkers of early cardiovascular aging

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