RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Ataxia-telangiectasia mutated and Rad3 related (ATR)-Seckel syndrome and autosomal recessive primary microcephaly (MCPH) syndrome share clinical features. RNA interference (RNAi) of MCPH1 have implicated the protein it encodes as a DNA-damage response protein that regulates the transcription of Chk1 and BRCA1, two genes involved in the response to DNA damage. Here, we report that truncating mutations observed in MCPH-syndrome patients do not impact on Chk1 or BRCA1 expression or early ATR-dependent damage-induced phosphorylation events. However, like ATR-Seckel syndrome cells, MCPH1-mutant cell lines show defective G2-M checkpoint arrest and nuclear fragmentation after DNA damage, and contain supernumerary mitotic centrosomes. MCPH1-mutant and ATR-Seckel cells also show impaired degradation of Cdc25A and fail to inhibit Cdc45 loading onto chromatin after replication arrest. Additionally, microcephalin interacts with Chk1. We conclude that MCPH1 has a function downstream of Chk1 in the ATR-signalling pathway. In contrast with ATR-Seckel syndrome cells, MCPH1-mutant cells have low levels of Tyr 15-phosphorylated Cdk1 (pY15-Cdk1) in S and G2 phases, which correlates with an elevated frequency of G2-like cells displaying premature chromosome condensation (PCC). Thus, MCPH1 also has an ATR-independent role in maintaining inhibitory Cdk1 phosphorylation, which prevents premature entry into mitosis.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Microcefalia/metabolismo , Mitose/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Malformações do Sistema Nervoso/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/fisiologia , Proteínas Mutadas de Ataxia Telangiectasia , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular , Quinase 1 do Ponto de Checagem , Proteínas do Citoesqueleto , Dano ao DNA/fisiologia , Genes cdc/fisiologia , Humanos , Microcefalia/genética , Microcefalia/fisiopatologia , Proteínas do Tecido Nervoso/genética , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Fosforilação , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Fosfatases cdc25/genética , Fosfatases cdc25/metabolismoRESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.