Assuntos
Acidentes por Quedas , Aorta/diagnóstico por imagem , Arteriopatias Oclusivas/diagnóstico por imagem , Arteriopatias Oclusivas/etiologia , Doença Aguda , Idoso de 80 Anos ou mais , Aorta/cirurgia , Arteriopatias Oclusivas/cirurgia , Angiografia por Tomografia Computadorizada , Feminino , Humanos , Traumatismos da Perna , Cuidados Paliativos , Fatores de RiscoRESUMO
Homologous recombination facilitates accurate repair of DNA double-strand breaks (DSBs) during the S and G2 phases of the cell cycle by using intact sister chromatids as sequence templates. Homologous recombination capacity is maximized in S and G2 by cyclin-dependent kinase (CDK) phosphorylation of CtIP, which subsequently interacts with BRCA1 and the Mre11-Rad50-NBS1 (MRN) complex. Here we show that, in human and mouse, Mre11 controls these events through a direct interaction with CDK2 that is required for CtIP phosphorylation and BRCA1 interaction in normally dividing cells. CDK2 binds the C terminus of Mre11, which is absent in an inherited allele causing ataxia telangiectasia-like disorder. This newly uncovered role for Mre11 does not require ATM activation or nuclease activities. Therefore, functions of MRN are not restricted to DNA damage responses but include regulating homologous recombination capacity during the normal mammalian cell cycle.
Assuntos
Proteínas de Transporte/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Endodesoxirribonucleases , Humanos , Proteína Homóloga a MRE11 , Camundongos , Camundongos Knockout , Fosforilação , Ligação Proteica , Mapeamento de Interação de Proteínas , Recombinação GenéticaRESUMO
The Mre11-Rad50-NBS1 (MRN) complex has many roles in response to DNA double-strand breaks, but its functions in repair by nonhomologous end joining (NHEJ) pathways are poorly understood. We have investigated requirements for MRN in class switch recombination (CSR), a programmed DNA rearrangement in B lymphocytes that requires NHEJ. To this end, we have engineered mice that lack the entire MRN complex in B lymphocytes or that possess an intact complex that harbors mutant Mre11 lacking DNA nuclease activities. MRN deficiency confers a strong defect in CSR, affecting both the classic and the alternative NHEJ pathways. In contrast, absence of Mre11 nuclease activities causes a milder phenotype, revealing a separation of function within the complex. We propose a model in which MRN stabilizes distant breaks and processes DNA termini to facilitate repair by both the classical and alternative NHEJ pathways.