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1.
Chemosphere ; 361: 142440, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38821133

RESUMEN

Plastic polymers were largely added with chemical substances to be utilized in the items and product manufacturing. The leachability of these substances is a matter of concern given the wide amount of plastic waste, particularly in terrestrial environments, where soil represents a sink for these novel contaminants and a possible pathway of human health risk. In this study, we integrated genetic, molecular, and behavioral approaches to comparatively evaluate toxicological effects of plastic leachates, virgin and oxodegradable polypropylene (PP) and polyethylene (PE), in Drosophila melanogaster, a novel in vivo model organism for environmental monitoring studies and (eco)toxicological research. The results of this study revealed that while conventional toxicological endpoints such as developmental times and longevity remain largely unaffected, exposure to plastic leachates induces chromosomal abnormalities and transposable element (TE) activation in neural tissues. The combined effects of DNA damage and TE mobilization contribute to genome instability and increase the likelihood of LOH events, thus potentiating tumor growth and metastatic behavior ofRasV12 clones. Collectively, these findings indicate that plastic leachates exert genotoxic effects in Drosophila thus highlighting potential risks associated with leachate-related plastic pollution and their implications for ecosystems and human health.


Asunto(s)
Daño del ADN , Drosophila melanogaster , Plásticos , Animales , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Plásticos/toxicidad , Polipropilenos/toxicidad , Polietileno/toxicidad , Aberraciones Cromosómicas/inducido químicamente , Monitoreo del Ambiente , Mutágenos/toxicidad , Elementos Transponibles de ADN , Pruebas de Mutagenicidad
2.
Cells ; 11(24)2022 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-36552798

RESUMEN

Exposure to artificial radio frequency electromagnetic fields (RF-EMFs) has greatly increased in recent years, thus promoting a growing scientific and social interest in deepening the biological impact of EMFs on living organisms. The current legislation governing the exposure to RF-EMFs is based exclusively on their thermal effects, without considering the possible non-thermal adverse health effects from long term exposure to EMFs. In this study we investigated the biological non-thermal effects of low-level indoor exposure to RF-EMFs produced by WiFi wireless technologies, using Drosophila melanogaster as the model system. Flies were exposed to 2.4 GHz radiofrequency in a Transverse Electromagnetic (TEM) cell device to ensure homogenous controlled fields. Signals were continuously monitored during the experiments and regulated at non thermal levels. The results of this study demonstrate that WiFi electromagnetic radiation causes extensive heterochromatin decondensation and thus a general loss of transposable elements epigenetic silencing in both germinal and neural tissues. Moreover, our findings provide evidence that WiFi related radiofrequency electromagnetic fields can induce reactive oxygen species (ROS) accumulation, genomic instability, and behavioural abnormalities. Finally, we demonstrate that WiFi radiation can synergize with RasV12 to drive tumor progression and invasion. All together, these data indicate that radiofrequency radiation emitted from WiFi devices could exert genotoxic effects in Drosophila and set the stage to further explore the biological effects of WiFi electromagnetic radiation on living organisms.


Asunto(s)
Drosophila melanogaster , Campos Electromagnéticos , Animales , Campos Electromagnéticos/efectos adversos , Drosophila melanogaster/genética , Elementos Transponibles de ADN/genética , Ondas de Radio/efectos adversos , Inestabilidad Genómica
3.
Genetics ; 222(2)2022 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-35946576

RESUMEN

In Drosophila chromosomal rearrangements can be maintained and are associated with karyotypic variability among populations from different geographic localities. The abundance of variability in gene arrangements among chromosomal arms is even greater when comparing more distantly related species and the study of these chromosomal changes has provided insights into the evolutionary history of species in the genus. In addition, the sequencing of genomes of several Drosophila species has offered the opportunity to establish the global pattern of genomic evolution, at both genetic and chromosomal level. The combined approaches of comparative analysis of syntenic blocks and direct physical maps on polytene chromosomes have elucidated changes in the orientation of genomic sequences and the difference between heterochromatic and euchromatic regions. Unfortunately, the centromeric heterochromatic regions cannot be studied using the cytological maps of polytene chromosomes because they are underreplicated and therefore reside in the chromocenter. In Drosophila melanogaster, a cytological map of the heterochromatin has been elaborated using mitotic chromosomes from larval neuroblasts. In the current work, we have expanded on that mapping by producing cytological maps of the mitotic heterochromatin in an additional 10 sequenced Drosophila species. These maps highlight 2 apparently different paths, for the evolution of the pericentric heterochromatin between the subgenera Sophophora and Drosophila. One path leads toward a progressive complexity of the pericentric heterochromatin (Sophophora) and the other toward a progressive simplification (Drosophila). These maps are also useful for a better understanding how karyotypes have been altered by chromosome arm reshuffling during evolution.


Asunto(s)
Proteínas de Drosophila , Heterocromatina , Animales , Drosophila/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Heterocromatina/genética , Cromosomas Politénicos
4.
Cells ; 11(8)2022 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-35455964

RESUMEN

Alzheimer's disease (AD) is an irreversible age-related neurodegenerative disorder clinically characterized by severe memory impairment, language deficits and cognitive decline. The major neuropathological hallmarks of AD include extracellular deposits of the ß-amyloid (Aß) peptides and cytoplasmic neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein. The accumulation of plaques and tangles in the brain triggers a cascade of molecular events that culminate in neuronal damage and cell death. Despite extensive research, our understanding of the molecular basis of AD pathogenesis remains incomplete and a cure for this devastating disease is still not available. A growing body of evidence in different experimental models suggests that poly(ADP-ribose) polymerase-1 (PARP-1) overactivation might be a crucial component of the molecular network of interactions responsible for AD pathogenesis. In this work, we combined genetic, molecular and biochemical approaches to investigate the effects of two different PARP-1 inhibitors (olaparib and MC2050) in Drosophila models of Alzheimer's disease by exploring their neuroprotective and therapeutic potential in vivo. We found that both pharmacological inhibition and genetic inactivation of PARP-1 significantly extend lifespan and improve the climbing ability of transgenic AD flies. Consistently, PARP-1 inhibitors lead to a significant decrease of Aß42 aggregates and partially rescue the epigenetic alterations associated with AD in the brain. Interestingly, olaparib and MC2050 also suppress the AD-associated aberrant activation of transposable elements in neuronal tissues of AD flies.


Asunto(s)
Enfermedad de Alzheimer , Fármacos Neuroprotectores , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Drosophila/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico
5.
iScience ; 25(1): 103702, 2022 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-35036881

RESUMEN

Huntington's disease (HD) is an autosomal dominant disorder with progressive motor dysfunction and cognitive decline. The disease is caused by a CAG repeat expansion in the IT15 gene, which elongates a polyglutamine stretch of the HD protein, Huntingtin. No therapeutic treatments are available, and new pharmacological targets are needed. Retrotransposons are transposable elements (TEs) that represent 40% and 30% of the human and Drosophila genomes and replicate through an RNA intermediate. Mounting evidence suggests that mammalian TEs are active during neurogenesis and may be involved in diseases of the nervous system. Here we show that TE expression and mobilization are increased in a Drosophila melanogaster HD model. By inhibiting TE mobilization with Reverse Transcriptase inhibitors, polyQ-dependent eye neurodegeneration and genome instability in larval brains are rescued and fly lifespan is increased. These results suggest that TE activation may be involved in polyQ-induced neurotoxicity and a potential pharmacological target.

6.
Chromosoma ; 130(2-3): 103-111, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34128099

RESUMEN

Heterochromatin protein 1 (HP1) is a non-histone chromosomal protein first identified in Drosophila as a major component of constitutive heterochromatin, required for stable epigenetic gene silencing in many species including humans. Over the years, several studies have highlighted additional roles of HP1 in different cellular processes including telomere maintenance, DNA replication and repair, chromosome segregation and, surprisingly, positive regulation of gene expression. In this review, we briefly summarize past research and recent results supporting the unexpected and emerging role of HP1 in activating gene expression. In particular, we discuss the role of HP1 in post-transcriptional regulation of mRNA processing because it has proved decisive in the control of germline stem cells homeostasis in Drosophila and has certainly added a new dimension to our understanding on HP1 targeting and functions in epigenetic regulation of stem cell behaviour.


Asunto(s)
Homólogo de la Proteína Chromobox 5 , Proteínas de Drosophila , Animales , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Epigénesis Genética , Regulación de la Expresión Génica , Heterocromatina/metabolismo , Humanos , Células Madre/metabolismo
7.
Proc Natl Acad Sci U S A ; 116(36): 17943-17950, 2019 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-31399546

RESUMEN

Previous studies have shown that heat shock stress may activate transposable elements (TEs) in Drosophila and other organisms. Such an effect depends on the disruption of a chaperone complex that is normally involved in biogenesis of Piwi-interacting RNAs (piRNAs), the largest class of germline-enriched small noncoding RNAs implicated in the epigenetic silencing of TEs. However, a satisfying picture of how chaperones could be involved in repressing TEs in germ cells is still unknown. Here we show that, in Drosophila, heat shock stress increases the expression of TEs at a posttranscriptional level by affecting piRNA biogenesis through the action of the inducible chaperone Hsp70. We found that stress-induced TE activation is triggered by an interaction of Hsp70 with the Hsc70-Hsp90 complex and other factors all involved in piRNA biogenesis in both ovaries and testes. Such interaction induces a displacement of all such factors to the lysosomes, resulting in a functional collapse of piRNA biogenesis. This mechanism has clear evolutionary implications. In the presence of drastic environmental changes, Hsp70 plays a key dual role in increasing both the survival probability of individuals and the genetic variability in their germ cells. The consequent increase of genetic variation in a population potentiates evolutionary plasticity and evolvability.


Asunto(s)
Elementos Transponibles de ADN , Proteínas HSP70 de Choque Térmico/metabolismo , Estrés Fisiológico , Activación Transcripcional , Evolución Molecular , Silenciador del Gen , Respuesta al Choque Térmico/genética , Modelos Biológicos , Unión Proteica , Interferencia de ARN
8.
Chromosoma ; 128(4): 503-520, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31203392

RESUMEN

Centromeres are epigenetically determined chromatin structures that specify the assembly site of the kinetochore, the multiprotein machinery that binds microtubules and mediates chromosome segregation during mitosis and meiosis. The centromeric protein A (CENP-A) and its Drosophila orthologue centromere identifier (Cid) are H3 histone variants that replace the canonical H3 histone in centromeric nucleosomes of eukaryotes. CENP-A/Cid is required for recruitment of other centromere and kinetochore proteins and its deficiency disrupts chromosome segregation. Despite the many components that are known to cooperate in centromere function, the complete network of factors involved in CENP-A recruitment remains to be defined. In Drosophila, the Trx-G proteins localize along the heterochromatin with specific patterns and some of them localize to the centromeres of all chromosomes. Here, we show that the Trx, Ash1, and CBP proteins are required for the correct chromosome segregation and that Ash1 and CBP mediate for Cid/CENP-A recruitment at centromeres through post-translational histone modifications. We found that centromeric H3 histone is consistently acetylated in K27 by CBP and that nej and ash1 silencing respectively causes a decrease in H3K27 acetylation and H3K4 methylation along with an impairment of Cid loading.


Asunto(s)
Proteína A Centromérica/metabolismo , Centrómero/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Factores de Transcripción/metabolismo , Factores de Transcripción p300-CBP/metabolismo , Acetilación , Animales , Drosophila melanogaster/metabolismo , Procesamiento Proteico-Postraduccional
9.
Sci Rep ; 9(1): 4372, 2019 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-30867469

RESUMEN

A very important open question in stem cells regulation is how the fine balance between GSCs self-renewal and differentiation is orchestrated at the molecular level. In the past several years much progress has been made in understanding the molecular mechanisms underlying intrinsic and extrinsic controls of GSC regulation but the complex gene regulatory networks that regulate stem cell behavior are only partially understood. HP1 is a dynamic epigenetic determinant mainly involved in heterochromatin formation, epigenetic gene silencing and telomere maintenance. Furthermore, recent studies have revealed the importance of HP1 in DNA repair, sister chromatid cohesion and, surprisingly, in positive regulation of gene expression. Here, we show that HP1 plays a crucial role in the control of GSC homeostasis in Drosophila. Our findings demonstrate that HP1 is required intrinsically to promote GSC self-renewal and progeny differentiation by directly stabilizing the transcripts of key genes involved in GSCs maintenance.


Asunto(s)
Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Drosophila/citología , Drosophila/metabolismo , Células Germinativas/metabolismo , Células Madre/metabolismo , Animales , Homólogo de la Proteína Chromobox 5 , Femenino , Células Germinativas/citología , Infertilidad Femenina/genética , Oogénesis/genética , Ovario/embriología , Ovario/metabolismo , Fenotipo , Interferencia de ARN , Procesamiento Postranscripcional del ARN , Células Madre/citología
10.
Stress ; 21(6): 575-579, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29996702

RESUMEN

Transposable elements (TEs) are conserved mobile genetic elements that are highly abundant in most eukaryotic genomes. Although the exact function of TEs is still largely unknown, it is increasingly clear that they are significantly modulated in response to stress in a wide range of organisms, either directly or indirectly through regulation of epigenetic silencing. We investigated the effect of repeated restraint stress (2 h a day, for 5 d) on transcription levels of LINE-1 (L1) retrotransposon in the brain of inbred BALB/c, DBA/2, C57BL/6N, and outbred CD1 mice. Repeated restraint stress induced strain and brain region-specific modulation of L1 activity. We observed a significant derepression of L1 transcription in the hippocampus (HIPP) of BALB/c mice and a significant downregulation in the hippocampus of C57BL/6N mice. No significant change in L1 expression was found in the other strains and brain regions. These findings indicate in mice the control of transposons expression as an additional mechanism in stress-induced pathophysiological responses, demonstrating that their regulation is highly dependent on the strain genetic background and the brain region. Lay summary Hippocampal expression of the transposon L1 is significantly altered by repeated restraint stress in mice. L1 modulation is not only region specific, but also strain dependent, suggesting that the genetic background is an important determinant of L1 response to environmental stimuli.


Asunto(s)
Encéfalo/metabolismo , Elementos Transponibles de ADN/genética , Elementos de Nucleótido Esparcido Largo/genética , Estrés Psicológico/genética , Amígdala del Cerebelo/metabolismo , Animales , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Corteza Prefrontal/metabolismo , Restricción Física , Estrés Psicológico/metabolismo
11.
Genetics ; 206(4): 1995-2006, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28576865

RESUMEN

One of the most fascinating scientific problems, and a subject of intense debate, is that of the mechanisms of biological evolution. In this context, Waddington elaborated the concepts of "canalization and assimilation" to explain how an apparently somatic variant induced by stress could become heritable through the germline in Drosophila He resolved this seemingly Lamarckian phenomenon by positing the existence of cryptic mutations that can be expressed and selected under stress. To investigate the relevance of such mechanisms, we performed experiments following the Waddington procedure, then isolated and fixed three phenotypic variants along with another induced mutation that was not preceded by any phenocopy. All the fixed mutations we looked at were actually generated de novo by DNA deletions or transposon insertions, highlighting a novel mechanism for the assimilation process. Our study shows that heat-shock stress produces both phenotypic variants and germline mutations, and suggests an alternative explanation to that of Waddington for the apparent assimilation of an acquired character. The selection of the variants, under stress, for a number of generations allows for the coselection of newly induced corresponding germline mutations, making the phenotypic variants appear heritable.


Asunto(s)
Evolución Molecular , Mutación de Línea Germinal , Modelos Genéticos , Selección Genética , Animales , Elementos Transponibles de ADN/genética , Drosophila/genética , Respuesta al Choque Térmico , Tasa de Mutación , Fenotipo
12.
Sci Rep ; 7: 41559, 2017 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-28139767

RESUMEN

Endoribonucleases participate in almost every step of eukaryotic RNA metabolism, acting either as degradative or biosynthetic enzymes. We previously identified the founding member of the Eukaryotic EndoU ribonuclease family, whose components display unique biochemical features and are flexibly involved in important biological processes, such as ribosome biogenesis, tumorigenesis and viral replication. Here we report the discovery of the CG3303 gene product, which we named DendoU, as a novel family member in Drosophila. Functional characterisation revealed that DendoU is essential for Drosophila viability and nervous system activity. Pan-neuronal silencing of dendoU resulted in fly immature phenotypes, highly reduced lifespan and dramatic motor performance defects. Neuron-subtype selective silencing showed that DendoU is particularly important in cholinergic circuits. At the molecular level, we unveiled that DendoU is a positive regulator of the neurodegeneration-associated protein dTDP-43, whose downregulation recapitulates the ensemble of dendoU-dependent phenotypes. This interdisciplinary work, which comprehends in silico, in vitro and in vivo studies, unveils a relevant role for DendoU in Drosophila nervous system physio-pathology and highlights that DendoU-mediated neurotoxicity is, at least in part, contributed by dTDP-43 loss-of-function.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/genética , Drosophila/metabolismo , Endorribonucleasas/genética , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Secuencia de Aminoácidos , Animales , Proteínas de Drosophila/genética , Endorribonucleasas/metabolismo , Perfilación de la Expresión Génica , Silenciador del Gen , Mutación con Pérdida de Función , Actividad Motora , Neuronas/metabolismo , Fenotipo , Análisis de Secuencia de ADN
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