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Molecular and Cellular Biology, June 2004, p. 5332-5339, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5332-5339.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Activation of a DNA Damage Checkpoint Response in a TAF1-Defective Cell Line

Ann M. Buchmann, Jeffrey R. Skaar, and James A. DeCaprio*

Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts

Received 19 December 2003/ Returned for modification 29 January 2004/ Accepted 26 March 2004

Although the link between transcription and DNA repair is well established, defects in the core transcriptional complex itself have not been shown to elicit a DNA damage response. Here we show that a cell line with a temperature-sensitive defect in TBP-associated factor 1 (TAF1), a component of the TFIID general transcription complex, exhibits hallmarks of an ATR-mediated DNA damage response. Upon inactivation of TAF1, ATR rapidly localized to subnuclear foci and contributed to the phosphorylation of several downstream targets, including p53 and Chk1, resulting in cell cycle arrest. The increase in p53 expression and the G1 phase arrest could be blocked by caffeine, an inhibitor of ATR. In addition, dominant negative forms of ATR but not ATM were able to override the arrest in G1. These results suggest that a defect in TAF1 can elicit a DNA damage response.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, Mayer 457, 44 Binney St., Boston, MA 02115. Phone: (617) 632-3825. Fax: (617) 632-4760. E-mail: james_decaprio{at}dfci.harvard.edu.

Molecular and Cellular Biology, June 2004, p. 5332-5339, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5332-5339.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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