RESUMO
Upon severe DNA damage a cellular signalling network initiates a cell death response through activating tumour suppressor p53 in association with promyelocytic leukaemia (PML) nuclear bodies. The deacetylase Sirtuin 1 (SIRT1) suppresses cell death after DNA damage by antagonizing p53 acetylation. To facilitate efficient p53 acetylation, SIRT1 function needs to be restricted. How SIRT1 activity is regulated under these conditions remains largely unclear. Here we provide evidence that SIRT1 activity is limited upon severe DNA damage through phosphorylation by the DNA damage-responsive kinase HIPK2. We found that DNA damage provokes interaction of SIRT1 and HIPK2, which phosphorylates SIRT1 at Serine 682 upon lethal damage. Furthermore, upon DNA damage SIRT1 and HIPK2 colocalize at PML nuclear bodies, and PML depletion abrogates DNA damage-induced SIRT1 Ser682 phosphorylation. We show that Ser682 phosphorylation inhibits SIRT1 activity and impacts on p53 acetylation, apoptotic p53 target gene expression and cell death. Mechanistically, we found that DNA damage-induced SIRT1 Ser682 phosphorylation provokes disruption of the complex between SIRT1 and its activator AROS. Our findings indicate that phosphorylation-dependent restriction of SIRT1 activity by HIPK2 shapes the p53 response.
Assuntos
Apoptose/genética , Proteínas de Transporte/biossíntese , Leucemia Promielocítica Aguda/genética , Proteínas Serina-Treonina Quinases/biossíntese , Sirtuína 1/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Acetilação , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Dano ao DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Promielocítica Aguda/patologia , Fosforilação , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Sirtuína 1/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
High-resolution dual X and gamma spectrometry has been optimized to improve the sensitivity in analyzing radioxenon from environmental samples, especially for the metastable isotopes (131Xem and 133Xem). The full-energy peak (FEP) efficiency curve in the 20-700 keV range has been established with a global uncertainty better than +/-3% using a Monte Carlo simulation. The minimum detectable activity concentrations (MDC) achievable at the laboratory for 131Xem, 133Xem, 133Xe and 135Xe are presented and the influence of 133Xe activity on the metastable radioxenon MDCs is evaluated.
Assuntos
Poluentes Radioativos do Ar/análise , Algoritmos , Microquímica/métodos , Monitoramento de Radiação/métodos , Espectrometria gama/métodos , Isótopos de Xenônio/análise , Radioisótopos de Xenônio/análise , Doses de Radiação , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
The use of liquid scintillation counting as a fundamental radionuclide standardisation method requires a correct description of the physical phenomena induced by the interaction of the ionising radiation with the liquid scintillator. In particular the standardisation of radionuclides decaying by electron capture as 55Fe and other electron-capture nuclides, requires the knowledge of total linear absorption coefficients of the liquid scintillator used for absolute activity measurement. Total linear absorption coefficient measurements have been undertaken using synchrotron radiation. Linear absorption coefficients of two widely used commercial liquid scintillators were measured in the 5.5-23 keV energy range. Small discrepancies were noted between theoretical and measured values of the Ultima-Gold mass attenuation coefficients for low energy photons.
