[Leter] Regulation of mitotic entry by microcephalin and its overlap with ATR signalling

Alderton, Gemma K, Galbiati, Laura, Griffith, Elen, Surinya, Kathatrina H, Neitzel, Heidemarie, Jackson, Andrew P, Jeggo, Penny A and O'Driscoll, Mark (2006) [Leter] Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Nature Cell Biology, 8 (7). pp. 725-733. ISSN 1465-7392

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Abstract

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 damage1,2. 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)3,4. Thus, MCPH1 also has an ATR-independent role in maintaining inhibitory Cdk1 phosphorylation, which prevents premature entry into mitosis.

Item Type: Article
Additional Information: I devised the concept that defective ATR-signalling was related to Primary Microcephaly and carried out most of the cellular analysis, mutagenesis and siRNA experiments. I am joint corresponding author on this work. This paper represents the first description of a defective DNA damage response in human Primary Microcephaly syndrome.
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: Penny Jeggo
Date Deposited: 06 Feb 2012 21:22
Last Modified: 11 Jun 2019 11:17
URI: http://sro.sussex.ac.uk/id/eprint/31005
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