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MBC in Press, published online ahead of print August 9, 2006
Mol. Biol. Cell 10.1091/mbc.E06-06-0516

A more recent version of this article appeared on October 1, 2006
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Submitted on June 12, 2006
Revised on July 28, 2006
Accepted on July 31, 2006

Top3 Processes Recombination Intermediates and Modulates Checkpoint Activity following DNA Damage

Hocine W. Mankouri and Ian D. Hickson

Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom

Monitoring Editor: Wendy Bickmore

Mutation of TOP3 in S. cerevisiae causes poor growth, hyper-recombination and a failure to fully activate DNA damage checkpoints in S-phase. Here, we report that overexpression of a dominant-negative allele of TOP3, TOP3Y356F, which lacks the catalytic (decatenation) activity of Top3, causes impaired S-phase progression and the persistence of abnormal DNA structures (X-shaped DNA molecules) following exposure to MMS. The impaired S-phase progression is due to a persistent checkpoint-mediated cell cycle delay, and can be overridden by addition of caffeine. Hence, the catalytic activity of Top3 is not required for DNA damage checkpoint activation, but is required for normal S-phase progression following DNA damage. We also present evidence that the checkpoint-mediated cell cycle delay and persistence of X-shaped DNA molecules resulting from overexpression of TOP3Y356F are downstream of Rad51 function. We propose that Top3 functions in S-phase to both process homologous recombination intermediates and modulate checkpoint activity.

Address correspondence to: Ian D. Hickson (ian.hickson{at}cancer.org.uk)




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