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Human Molecular Genetics Advance Access published online on October 20, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh335
© 2004 by Oxford University Press
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Article

Seckel syndrome exhibits cellular features demonstrating defects in the ATR signalling pathway

Gemma K. Alderton 1, Hans Joenje 2, Raymonda Varon 3, Anders D. Børglum 4, Penny A. Jeggo 1*, and Mark O'Driscoll 1

1 Genome Damage and Stability Centre, University of Sussex, East Sussex, BN1 9RQ, UK
2 Department of Clinical Genetics and Human Genetics, VU University Medical Center, Van der Boechorststraat 7, NL-1081 BT, Amsterdam, The Netherlands
3 Institute of Human Genetics, Charite-University Medicine Berlin, Augustenburger platz 1, Berlin 13353, Germany
4 Institute of Human Genetics, University of Aarhus, The Bartholin Building, DK-8000 Aarhus C, Denmark

* To whom correspondence should be addressed.
Penny A. Jeggo, E-mail: p.a.jeggo{at}sussex.ac.uk


  Abstract

To date, the only reported genetic defect identified in the developmental disorder, Seckel syndrome, is a mutation in ataxia telangiectasia and Rad3-related protein (ATR). Seckel syndrome is clinically and genetically heterogeneous and whether defects in ATR significantly contribute to Seckel syndrome is unclear. Firstly, we characterize ATR-Seckel cells for their response to DNA damage. ATR-Seckel cells display impaired phosphorylation of ATR-dependent substrates, impaired G2/M checkpoint arrest and elevated micronucleus formation following exposure to UV and agents that cause replication stalling. We describe a novel phenotype, designated nuclear fragmentation, that occurs following replication arrest. Finally, we report that ATR-Seckel cells have an endogenously increased number of centrosomes in mitotic cells demonstrating a novel role for ATR in regulating centrosome stability. We exploit these phenotypes to examine cell lines derived from additional unrelated Seckel syndrome patients. We show that impaired phosphorylation of ATR-dependent substrates is a common but not invariant feature of Seckel syndrome cell lines. In contrast, all cell lines displayed defective G2/M arrest, increased levels of nuclear fragmentation and micronucleus formation following exposure to agents that cause replication stalling. All the Seckel syndrome cell lines examined showed increased endogenous centrosome numbers. Whilst ATR cDNA can complement the defects in ATR-Seckel cells, it failed to complement any of the additional cell lines. We conclude that Seckel syndrome represents a further damage response disorder that is uniquely associated with defects in the ATR signalling pathway resulting in failed checkpoint arrest following exposure to replication fork stalling.


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