Activation of a DNA damage checkpoint response in a TAF1-defective cell line.
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 G(1) 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 G(1). These results suggest that a defect in TAF1 can elicit a DNA damage response.
Buchmann
Ann M
AM
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Skaar
Jeffrey R
JR
DeCaprio
James A
JA
D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004249:DNA Damage; D004789:Enzyme Activation; D015870:Gene Expression; D016158:Genes, p53; D051548:Histone Acetyltransferases; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics* / Q000378:metabolism*; D013696:Temperature; D035362:Transcription Factor TFIID / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism
D018797:Cell Cycle Proteins; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D016159:Tumor Suppressor Protein p53; D012694:Serine; D051548:Histone Acetyltransferases; D017346:Protein Serine-Threonine Kinases; C069001:TATA-binding protein associated factor 250 kDa