Skip Navigation


Human Molecular Genetics Advance Access originally published online on July 28, 2008
Human Molecular Genetics 2008 17(20):3247-3253; doi:10.1093/hmg/ddn220
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow All Versions of this Article:
17/20/3247    most recent
ddn220v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Stiff, T.
Right arrow Articles by Jeggo, P. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stiff, T.
Right arrow Articles by Jeggo, P. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Replication independent ATR signalling leads to G2/M arrest requiring Nbs1, 53BP1 and MDC1

Tom Stiff1, Karen Cerosaletti2, Patrick Concannon3, Mark O'Driscoll1 and Penny A. Jeggo1,*

1 Genome Damage and Stability Centre, University of Sussex, Brighton, East Sussex BN1 9RQ, UK 2 Molecular Genetics, Benaroya Research Institute, Seattle, WA 98101, USA 3 Department of Biochemistry & Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA

* To whom correspondence should be addressed. Tel: +44 1273678482; Fax: +44 1273678121; Email: p.a.jeggo{at}sussex.ac.uk

Received July 11, 2008; Revised July 11, 2008; Accepted July 22, 2008

Ataxia telangiectasia and Rad3-related (ATR) is a phosphoinositol-3-kinase like kinase (PIKK) that initiates a signal transduction response to replication fork stalling. Defects in ATR signalling have been reported in several disorders characterized by microcephaly and growth delay. Here, we gain insight into factors influencing the ATR signalling pathway and consider how they can be exploited for diagnostic purposes. Activation of ATR at stalled replication forks leads to intra-S and G2/M phase checkpoint arrest. ATR also phosphorylates {gamma}-H2AX at single-stranded (ss) DNA regions generated during nucleotide excision repair (NER) in non-replicating cells, but the critical analysis of any functional consequence has not been reported. Here, we show that UV irradiation of G2 phase cells causes ATR-dependent but replication-independent G2/M checkpoint arrest. This process requires the Nbs1 N-terminus encompassing the FHA and BRCT domains but not the Nbs1 C-terminus in contrast to ATM-dependent activation of G2/M arrest in response to ionizing radiation. Thus, Nbs1 has a function in ATR signalling in a manner distinct to any role at stalled replication forks. Replication-independent ATR signalling also requires the mediator proteins, 53BP1 and MDC1, providing direct evidence for their role in ATR signalling, but not H2AX. Finally, the process is activated in Cockayne's syndrome but not Xeroderma pigmentosum group A cells providing evidence that ssDNA regions generated during NER are the ATR-pathway-specific activating lesion. Replication-independent G2/M checkpoint arrest represents a suitable assay to specifically identify patients with defective ATR signalling, including Seckel syndrome, Nijmegen breakage syndrome and MCPH-1-dependent primary microcephaly.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Nucleic Acids ResHome page
J.-H. Choi, L. A. Lindsey-Boltz, and A. Sancar
Cooperative activation of the ATR checkpoint kinase by TopBP1 and damaged DNA
Nucleic Acids Res., April 1, 2009; 37(5): 1501 - 1509.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.