RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
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.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Microcefalia/metabolismo , Mitosis/fisiología , Proteínas del Tejido Nervioso/metabolismo , Malformaciones del Sistema Nervioso/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/fisiología , Proteínas de la Ataxia Telangiectasia Mutada , Proteína Quinasa CDC2/genética , Proteína Quinasa CDC2/metabolismo , Proteínas de Ciclo Celular/genética , Línea Celular , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Proteínas del Citoesqueleto , Daño del ADN/fisiología , Genes cdc/fisiología , Humanos , Microcefalia/genética , Microcefalia/fisiopatología , Proteínas del Tejido Nervioso/genética , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/fisiopatología , Fosforilación , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Fosfatasas cdc25/genética , Fosfatasas cdc25/metabolismoRESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.
RESUMEN
Highlights from the Science family of journals.