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Originally published as Genetics Published Articles Ahead of Print on September 30, 2004.
Genetics, Vol. 169, 65-75, January 2005, Copyright © 2005
doi:10.1534/genetics.104.030940
Ccr4-Not Complex mRNA Deadenylase Activity Contributes to DNA Damage Responses in Saccharomyces cerevisiae
Ana Traven*,
Andrew Hammet*,1,
Nora Tenis*,
Clyde L. Denis
and
Jörg Heierhorst*,
,2
* St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia
Department of Biochemistry and Molecular Biology, University of New Hampshire, Durham, New Hampshire 03824
Department of Medicine SVH, The University of Melbourne, Fitzroy, Victoria 3065, Australia
2 Corresponding author: St. Vincent's Institute of Medical Research, 9 Princes St., Fitzroy, Victoria 3065, Australia.
E-mail: jheierhorst{at}svi.edu.au
DNA damage checkpoints regulate gene expression at the transcriptional and post-transcriptional level. Some components of the yeast Ccr4-Not complex, which regulates transcription as well as transcript turnover, have previously been linked to DNA damage responses, but it is unclear if this involves transcriptional or post-transcriptional functions. Here we show that CCR4 and CAF1, which together encode the major cytoplasmic mRNA deadenylase complex, have complex genetic interactions with the checkpoint genes DUN1, MRC1, RAD9, and RAD17 in response to DNA-damaging agents hydroxyurea (HU) and methylmethane sulfonate (MMS). The exonuclease-inactivating ccr4-1 point mutation mimics ccr4
phenotypes, including synthetic HU hypersensitivity with dun1, demonstrating that Ccr4-Not mRNA deadenylase activity is required for DNA damage responses. However, ccr4 and caf1 DNA damage phenotypes and genetic interactions with checkpoint genes are not identical, and deletions of some Not components that are believed to predominantly function at the transcriptional level rather than mRNA turnover, e.g., not5, also lead to increased DNA damage sensitivity and synthetic HU hypersensitivity with dun1. Taken together, our data thus suggest that both transcriptional and post-transcriptional functions of the Ccr4-Not complex contribute to the DNA damage response affecting gene expression in a complex manner.
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