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Molecular and Cellular Biology, December 2006, p. 9256-9267, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01125-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

ATM and ATR Pathways Signal Alternative Splicing of Drosophila TAF1 Pre-mRNA in Response to DNA Damage{triangledown}

Rebeccah J. Katzenberger,{dagger} Matthew S. Marengo,{dagger} and David A. Wassarman*

University of Wisconsin School of Medicine and Public Health, Department of Pharmacology, Molecular and Cellular Pharmacology Program, 1300 University Avenue, Madison, Wisconsin 53706

Received 22 June 2006/ Returned for modification 1 August 2006/ Accepted 21 September 2006

Alternative pre-mRNA splicing is a major mechanism utilized by eukaryotic organisms to expand their protein-coding capacity. To examine the role of cell signaling in regulating alternative splicing, we analyzed the splicing of the Drosophila melanogaster TAF1 pre-mRNA. TAF1 encodes a subunit of TFIID, which is broadly required for RNA polymerase II transcription. We demonstrate that TAF1 alternative splicing generates four mRNAs, TAF1-1, TAF1-2, TAF1-3, and TAF1-4, of which TAF1-2 and TAF1-4 encode proteins that directly bind DNA through AT hooks. TAF1 alternative splicing was regulated in a tissue-specific manner and in response to DNA damage induced by ionizing radiation or camptothecin. Pharmacological inhibitors and RNA interference were used to demonstrate that ionizing-radiation-induced upregulation of TAF1-3 and TAF1-4 splicing in S2 cells was mediated by the ATM (ataxia-telangiectasia mutated) DNA damage response kinase and checkpoint kinase 2 (CHK2), a known ATM substrate. Similarly, camptothecin-induced upregulation of TAF1-3 and TAF1-4 splicing was mediated by ATR (ATM-RAD3 related) and CHK1. These findings suggest that inducible TAF1 alternative splicing is a mechanism to regulate transcription in response to developmental or DNA damage signals and provide the first evidence that the ATM/CHK2 and ATR/CHK1 signaling pathways control gene expression by regulating alternative splicing.

* Corresponding author. Mailing address: University of Wisconsin School of Medicine and Public Health, Department of Pharmacology, 1300 University Avenue, Madison, WI 53706. Phone: (608) 262-6648. Fax: (608) 262-1257. E-mail: dawassarman{at}wisc.edu.

{triangledown} Published ahead of print on 9 October 2006.

{dagger} These authors contributed equally to the paper.

Molecular and Cellular Biology, December 2006, p. 9256-9267, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01125-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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