Cancer, birth defects and aging are all thought to result from of an accumulation of genetic damage. Cells respond to the challenge of DNA damage by activating a protein kinase cascade that causes cell cycle arrest and the induction of repair genes. Alterations in either of these responses lead to human disease. Kinases in these pathways have been identified, however, their transcription factor targets have remained elusive. We have identified potential targets. Through our genetic study of the TATA-box binding protein associated factors (yTAFIIS) from the budding yeast Saccharomyces cerevisiae, we have discovered that yTAFIIS are required for the cellular response to DNA damage and damage- induced transcription. This is a significant discovery, because the in vivo functions of TAFIIS are largely unknown. Biochemical studies have implicated them as being important for the control of transcription from all promoters, and they are thought to do so by acting as coactivators and promoter selectivity factors. However, analysis of TAFII mutants in vivo in both yeast and mammalian systems have challenged this model. Mutation of multiple yeast TAFIIS, and mutation of the largest mammalian TAFII, do not lead to global defects in transcription, but lead to cell cycle defects and alterations in transcription of a select number of genes. Previous work identified two classes of genes that are dependent upon TAF145 for transcription. Most surprisingly, TAF145 determinants are not activator binding sites, but core promoter elements, leaving the issue of what signals are acting through TAFIIS an open question. We have found that the transcription of DNA damage response genes requires multiple TAFII subunits, which makes their regulation distinct from the previously identified gene classes. This proposal will extend these preliminary observations by characterizing the role of TAFIIS in the regulation of DNA damage responsive genes and explore the signaling pathways that mediate their activities. These studies will identify the determinants of TAFII-dependent genes, the cellular signals controlling TAFII function, and attempt to establish TAFIIS as the transcription factor targets of the DNA damage protein kinase cascade. This work will impact the fields of transcription, DNA damage and cell cycle control.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular Biology Study Section (MBY)
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Tompkins, Laurie
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Pennsylvania State University
Schools of Arts and Sciences
University Park
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Miller, Jason E; Zhang, Liye; Jiang, Haoyang et al. (2018) Genome-Wide Mapping of Decay Factor-mRNA Interactions in Yeast Identifies Nutrient-Responsive Transcripts as Targets of the Deadenylase Ccr4. G3 (Bethesda) 8:315-330
Crickard, John B; Lee, Jaehyoun; Lee, Tae-Hee et al. (2017) The elongation factor Spt4/5 regulates RNA polymerase II transcription through the nucleosome. Nucleic Acids Res 45:6362-6374
Crickard, J Brooks; Fu, Jianhua; Reese, Joseph C (2016) Biochemical Analysis of Yeast Suppressor of Ty 4/5 (Spt4/5) Reveals the Importance of Nucleic Acid Interactions in the Prevention of RNA Polymerase II Arrest. J Biol Chem 291:9853-70
Dutta, Arnob; Babbarwal, Vinod; Fu, Jianhua et al. (2015) Ccr4-Not and TFIIS Function Cooperatively To Rescue Arrested RNA Polymerase II. Mol Cell Biol 35:1915-25
Zheng, Suting; Crickard, J Brooks; Srikanth, Abhinaya et al. (2014) A highly conserved region within H2B is important for FACT to act on nucleosomes. Mol Cell Biol 34:303-14
Collart, Martine A; Reese, Joseph C (2014) Gene expression as a circular process: cross-talk between transcription and mRNA degradation in eukaryotes; International University of Andalusia (UNIA) Baeza, Spain. RNA Biol 11:320-3
Babbarwal, Vinod; Fu, Jianhua; Reese, Joseph C (2014) The Rpb4/7 module of RNA polymerase II is required for carbon catabolite repressor protein 4-negative on TATA (Ccr4-not) complex to promote elongation. J Biol Chem 289:33125-30
Reese, Joseph C (2013) The control of elongation by the yeast Ccr4-not complex. Biochim Biophys Acta 1829:127-33
Bhargava, Purnima; Reese, Joseph C (2013) Transcription by Odd Pols. Biochim Biophys Acta 1829:249-50
Miller, Jason E; Reese, Joseph C (2012) Ccr4-Not complex: the control freak of eukaryotic cells. Crit Rev Biochem Mol Biol 47:315-33

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