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First published online 22 March 2005
doi: 10.1242/jcs.01728

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STAT-1 facilitates the ATM activated checkpoint pathway following DNA damage

Paul A. Townsend^1,*, Mark S. Cragg², Sean M. Davidson¹, James McCormick¹, Sean Barry¹, Kevin M. Lawrence¹, Richard A. Knight¹, Michael Hubank³, Phang-Lang Chen⁴, David S. Latchman¹ and Anastasis Stephanou^1,

¹ Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK
³ Molecular Haematology, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK
² Cancer Sciences Division, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, UK
⁴ Department of Molecular Medicine and Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA

Author for correspondence (e-mail: a.stephanou{at}ich.ucl.ac.uk)

Accepted 13 January 2005

STAT-1 plays a role in mediating stress responses to various stimuli and has also been implied to be a tumour suppressor. Here, we report that STAT-1-deficient cells have defects both in intra-S-phase and G2-M checkpoints in response to DNA damage. Interestingly, STAT-1-deficient cells showed reduced Chk2 phosphorylation on threonine 68 (Chk2^-T68) following DNA damage, suggesting that STAT-1 might function in the ATM-Chk2 pathway. Moreover, the defects in Chk2^-T68 phosphorylation in STAT-1-deficient cells also correlated with reduced degradation of Cdc25A compared with STAT-1-expressing cells after DNA damage. We also show that STAT-1 is required for ATM-dependent phosphorylation of NBS1 and p53 but not for BRCA1 or H2AX phosphorylation following DNA damage. Expression levels of BRCT mediator/adaptor proteins MDC1 and 53BP1, which are required for ATM-mediated pathways, are reduced in cells lacking STAT-1. Enforced expression of MDC1 into STAT-1-deficient cells restored ATM-mediated phosphorylation of downstream substrates. These results imply that STAT-1 plays a crucial role in the DNA-damage-response by regulating the expression of 53BP1 and MDC1, factors known to be important for mediating ATM-dependent checkpoint pathways.

Key words: ATM, Cell cycle, Chk2, 53BP1, MDC1, STAT-1

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