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1.
EMBO Rep ; 21(2): e48222, 2020 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-31867888

RESUMEN

SMC5/6 function in genome integrity remains elusive. Here, we show that SMC5 dysfunction in avian DT40 B cells causes mitotic delay and hypersensitivity toward DNA intra- and inter-strand crosslinkers (ICLs), with smc5 mutants being epistatic to FANCC and FANCM mutations affecting the Fanconi anemia (FA) pathway. Mutations in the checkpoint clamp loader RAD17 and the DNA helicase DDX11, acting in an FA-like pathway, do not aggravate the damage sensitivity caused by SMC5 dysfunction in DT40 cells. SMC5/6 knockdown in HeLa cells causes MMC sensitivity, increases nuclear bridges, micronuclei, and mitotic catastrophes in a manner similar and non-additive to FANCD2 knockdown. In both DT40 and HeLa systems, SMC5/6 deficiency does not affect FANCD2 ubiquitylation and, unlike FANCD2 depletion, RAD51 focus formation. SMC5/6 components further physically interact with FANCD2-I in human cells. Altogether, our data suggest that SMC5/6 functions jointly with the FA pathway to support genome integrity and DNA repair and may be implicated in FA or FA-related human disorders.


Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Anemia de Fanconi , ARN Helicasas DEAD-box , Daño del ADN/genética , ADN Helicasas/genética , Reparación del ADN/genética , Anemia de Fanconi/genética , Inestabilidad Genómica , Células HeLa , Humanos
2.
Cell Death Differ ; 28(4): 1159-1173, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33723374

RESUMEN

Fanconi anaemia (FA) is the most frequent inherited bone marrow failure syndrome, due to mutations in genes encoding proteins involved in replication fork protection, DNA interstrand crosslink repair and replication rescue through inducing double-strand break repair and homologous recombination. Clinically, FA is characterised by aplastic anaemia, congenital defects and cancer predisposition. In in vitro studies, FA cells presented hallmarks defining senescent cells, including p53-p21 axis activation, altered telomere length, mitochondrial dysfunction, chromatin alterations, and a pro-inflammatory status. Senescence is a programme leading to proliferation arrest that is involved in different physiological contexts, such as embryogenesis, tissue remodelling and repair and guarantees tumour suppression activity. However, senescence can become a driving force for developmental abnormalities, aging and cancer. Herein, we summarise the current knowledge in the field to highlight the mutual relationships between FA and senescence that lead us to consider FA not only as a DNA repair and chromosome fragility syndrome but also as a "senescence syndrome".


Asunto(s)
Senescencia Celular/genética , Inestabilidad Cromosómica , Reparación del ADN , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Anemia de Fanconi/genética , Animales , Roturas del ADN de Doble Cadena , Replicación del ADN , Anemia de Fanconi/metabolismo , Proteínas del Grupo de Complementación de la Anemia de Fanconi/metabolismo , Humanos , Fenotipo
3.
Sci Rep ; 9(1): 17024, 2019 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-31745226

RESUMEN

Fanconi Anemia (FA), due to the loss-of-function of the proteins that constitute the FANC pathway involved in DNA replication and genetic stability maintainance, is a rare genetic disease featuring bone marrow failure, developmental abnormalities and cancer predisposition. Similar clinical stigmas have also been associated with alterations in the senescence program, which is activated in physiological or stress situations, including the unscheduled, chronic, activation of an oncogene (oncogene induced senescence, OIS). Here, we wanted to determine the crosstalk, if any, between the FANC pathway and the OIS process. OIS was analyzed in two known cellular models, IMR90-hTERT/ER:RASG12V and WI38-hTERT/ER:GFP:RAF1, harboring 4-hydroxytamoxifen-inducible oncogenes. We observed that oncogene activation induces a transitory increase of both FANCA and FANCD2 as well as FANCD2 monoubiquitination, readout of FANC pathway activation, followed by their degradation. FANCD2 depletion, which leads to a pre-senescent phenotype, anticipates OIS progression. Coherently, FANCD2 overexpression or inhibition of its proteosomal-dependent degradation slightly delays OIS progression. The pro-senescence protease cathepsin L, which activation is anticipated during OIS in FANCD2-depleted cells, also participates to FANCD2 degradation. Our results demonstrate that oncogene activation is first associated with FANCD2 induction and activation, which may support initial cell proliferation, followed by its degradation/downregulation when OIS proceeds.


Asunto(s)
Senescencia Celular/genética , Proteína del Grupo de Complementación A de la Anemia de Fanconi/metabolismo , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/metabolismo , Anemia de Fanconi/genética , Catepsina L/metabolismo , Línea Celular , Proliferación Celular/genética , Transformación Celular Neoplásica/genética , Daño del ADN/genética , Reparación del ADN/genética , Replicación del ADN/genética , Anemia de Fanconi/patología , Humanos , Especies Reactivas de Oxígeno/metabolismo , Ubiquitinación
4.
Sci Transl Med ; 8(369): 369ra177, 2016 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-27974665

RESUMEN

Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesized that gene expression from gonosomes (sex chromosomes) might play an important role. We demonstrate that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit from two X chromosomes. The gonosomal protein phosphatase 2 regulatory subunit B, beta (PPP2R3B) gene is located on the pseudoautosomal region (PAR) of the X chromosome in females and the Y chromosome in males. We observed that, despite its location on the PAR that predicts equal dosage across genders, PPP2R3B expression was lower in males than in females and was independently correlated with poor clinical outcome. PPP2R3B codes for the PR70 protein, a regulatory substrate-recognizing subunit of protein phosphatase 2A. PR70 decreased melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing the cell division cycle 6 (CDC6)-chromatin licensing and DNA replication factor 1 (CDT1) interaction, which delays the firing of origins of DNA replication. Hence, PR70 functionally behaves as an X-linked tumor suppressor gene.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Melanoma/metabolismo , Proteínas Nucleares/metabolismo , Proteína Fosfatasa 2/metabolismo , Neoplasias Cutáneas/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Aberraciones Cromosómicas , Cromosomas Humanos X , Replicación del ADN , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Células HEK293 , Humanos , Masculino , Melanoma/genética , Ratones , Metástasis de la Neoplasia , Trasplante de Neoplasias , Pronóstico , Proteína Fosfatasa 2/genética , Factores Sexuales
5.
Eur J Hum Genet ; 10(3): 157-61, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11973618

RESUMEN

Emery-Dreifuss muscular dystrophy (EDMD) is characterised by early contractures, slowly progressive muscle wasting and weakness with a distinctive humero-peroneal distribution and cardiac conduction defects leading to dilated cardiomyopathy. The genes known to be responsible for EDMD encode proteins associated with the nuclear envelope: the emerin and the lamins A and C.


Asunto(s)
Distrofia Muscular de Emery-Dreifuss/diagnóstico , Distrofia Muscular de Emery-Dreifuss/genética , Genes Dominantes , Humanos , Laminas , Proteínas de la Membrana/genética , Modelos Genéticos , Mutación , Proteínas Nucleares/genética , Timopoyetinas/genética , Cromosoma X
7.
Hum Mol Genet ; 14(1): 155-69, 2005 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-15548545

RESUMEN

Laminopathies are a group of disorders caused by mutations in the LMNA gene encoding A-type lamins, components of the nuclear lamina. Three of these disorders affect specifically the skeletal and/or cardiac muscles, and their pathogenic mechanisms are still unknown. We chose the LMNA H222P missense mutation identified in a family with autosomal dominant Emery-Dreifuss muscular dystrophy, one of the striated muscle-specific laminopathies, to create a faithful mouse model of this type of laminopathy. The mutant mice exhibit overtly normal embryonic development and sexual maturity. At adulthood, male homozygous mice display reduced locomotion activity with abnormal stiff walking posture and all of them die by 9 months of age. As for cardiac phenotype, they develop chamber dilation and hypokinesia with conduction defects. These abnormal skeletal and cardiac features were also observed in the female homozygous mice but with a later-onset than in males. Histopathological analysis of the mice revealed muscle degeneration with fibrosis associated with dislocation of heterochromatin and activation of Smad signalling in heart and skeletal muscles. These results demonstrate that LmnaH222P/H222P mice represent a good model for studying laminopathies affecting striated muscles as they develop a dystrophic condition of both skeletal and cardiac muscles similar to the human diseases.


Asunto(s)
Cardiomiopatía Dilatada/genética , Modelos Animales de Enfermedad , Lamina Tipo A/genética , Distrofia Muscular Animal/genética , Distrofia Muscular de Emery-Dreifuss/genética , Mutación Missense/genética , Animales , Cardiomiopatía Dilatada/patología , Humanos , Ratones , Distrofia Muscular Animal/patología , Distrofia Muscular de Emery-Dreifuss/patología
8.
Am J Hum Genet ; 71(2): 426-31, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12075506

RESUMEN

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder, characterized by postnatal growth retardation, craniofacial anomalies, skeletal malformations, and mottled cutaneous pigmentation. The LMNA gene encoding two nuclear envelope proteins (lamins A and C [lamin A/C]) maps to chromosome 1q21 and has been associated with five distinct pathologies, including Dunnigan-type familial partial lipodystrophy, a condition that is characterized by subcutaneous fat loss and is invariably associated with insulin resistance and diabetes. Since patients with MAD frequently have partial lipodystrophy and insulin resistance, we hypothesized that the disease may be caused by mutations in the LMNA gene. We analyzed five consanguineous Italian families and demonstrated linkage of MAD to chromosome 1q21, by use of homozygosity mapping. We then sequenced the LMNA gene and identified a homozygous missense mutation (R527H) that was shared by all affected patients. Patient skin fibroblasts showed nuclei that presented abnormal lamin A/C distribution and a dysmorphic envelope, thus demonstrating the pathogenic effect of the R527H LMNA mutation.


Asunto(s)
Anomalías Múltiples/genética , Mutación , Proteínas Nucleares/genética , Anomalías Múltiples/etiología , Fibroblastos , Técnica del Anticuerpo Fluorescente , Humanos , Lamina Tipo A , Laminas , Masculino , Repeticiones de Microsatélite , Linaje , Análisis de Secuencia de ADN
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