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1.
Trends Biochem Sci ; 47(6): 506-517, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35440402

RESUMO

Telomeres are chromosome-capping structures that protect ends of the linear genome from DNA damage sensors. However, these structures present obstacles during DNA replication. Incomplete telomere replication accelerates telomere shortening and limits replicative lifespan. Therefore, continued proliferation under conditions of replication stress requires a means of telomere repair, particularly in the absence of telomerase. It was recently revealed that replication stress triggers break-induced replication (BIR) and mitotic DNA synthesis (MiDAS) at mammalian telomeres; however, these mechanisms are error prone and primarily utilized in tumorigenic contexts. In this review article, we discuss the consequences of replication stress at telomeres and how use of available repair pathways contributes to genomic instability. Current research suggests that fragile telomeres are ultimately tumor-suppressive and thus may be better left unrepaired.


Assuntos
Telomerase , Telômero , Animais , Reparo do DNA , Replicação do DNA , Instabilidade Genômica , Mamíferos , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Telômero/metabolismo , Homeostase do Telômero
2.
Thorax ; 73(5): 489-492, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29382801

RESUMO

Familial pulmonary fibrosis is associated with loss-of-function mutations in telomerase reverse transcriptase (TERT) and short telomeres. Interstitial lung diseases have become the leading indication for lung transplantation in the USA, and recent data indicate that pathogenic mutations in telomerase may cause unfavourable outcomes following lung transplantation. Although a rare occurrence, solid organ transplant recipients who develop acute graft-versus-host disease (GVHD) have very poor survival. This case report describes the detection of a novel mutation in TERT in a patient who had lung transplantation for familial pulmonary fibrosis and died from complications of acute GVHD.


Assuntos
Doença Enxerto-Hospedeiro/etiologia , Transplante de Pulmão/efeitos adversos , Fibrose Pulmonar/genética , Telomerase/genética , Doença Aguda , Evolução Fatal , Feminino , Doença Enxerto-Hospedeiro/patologia , Humanos , Mutação , Fibrose Pulmonar/cirurgia , Telomerase/metabolismo
3.
Science ; 381(6659): 771-778, 2023 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-37590346

RESUMO

Protection of telomeres 1 (POT1) is the 3' single-stranded overhang-binding telomeric protein that prevents an ataxia telangiectasia and Rad3-related (ATR) DNA damage response (DDR) at chromosome ends. What precludes the DDR machinery from accessing the telomeric double-stranded-single-stranded junction is unknown. We demonstrate that human POT1 binds this junction by recognizing the phosphorylated 5' end of the chromosome. High-resolution crystallographic structures reveal that the junction is capped by POT1 through a "POT-hole" surface, the mutation of which compromises junction protection in vitro and telomeric 5'-end definition and DDR suppression in human cells. Whereas both mouse POT1 paralogs bind the single-stranded overhang, POT1a, not POT1b, contains a POT-hole and binds the junction, which explains POT1a's sufficiency for end protection. Our study shifts the paradigm for DDR suppression at telomeres by highlighting the importance of protecting the double-stranded-single-stranded junction.


Assuntos
DNA , Complexo Shelterina , Proteínas de Ligação a Telômeros , Telômero , Animais , Humanos , Camundongos , Cristalografia , DNA/química , DNA/metabolismo , Mutação , Complexo Shelterina/química , Complexo Shelterina/genética , Complexo Shelterina/metabolismo , Telômero/química , Telômero/metabolismo , Proteínas de Ligação a Telômeros/química , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo
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