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1.
Hum Mutat ; 39(2): 255-265, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29105242

RESUMO

Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5' incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.


Assuntos
Síndrome de Cockayne/genética , Proteínas de Ligação a DNA/genética , Xeroderma Pigmentoso/genética , Actinas/genética , Idoso , Reparo do DNA/genética , Proteínas de Ligação a DNA/química , Anemia de Fanconi/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Lamina Tipo A/genética , Masculino , Pessoa de Meia-Idade , Linhagem
2.
Aging Cell ; 14(4): 644-58, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25754370

RESUMO

The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1(-/Δ) mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1(-/∆) mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.


Assuntos
Envelhecimento/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Dasatinibe/farmacologia , Osteoporose/prevenção & controle , Quercetina/farmacologia , Transcriptoma , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/patologia , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Senescência Celular/genética , Classe I de Fosfatidilinositol 3-Quinases , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Combinação de Medicamentos , Endonucleases/genética , Endonucleases/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Efrinas/genética , Efrinas/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Perfilação da Expressão Gênica , Coração/efeitos dos fármacos , Coração/fisiopatologia , Disco Intervertebral/química , Disco Intervertebral/efeitos dos fármacos , Disco Intervertebral/patologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Knockout , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidor 2 de Ativador de Plasminogênio/genética , Inibidor 2 de Ativador de Plasminogênio/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
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