REGULATION OF DNA DAMAGE INDUCED GENES BY YEAST TAFIIS

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date1/1/9912/31/06

Funding

  • National Institute of General Medical Sciences: $300,511.00
  • National Institute of General Medical Sciences: $75,380.00
  • National Institute of General Medical Sciences: $49,465.00
  • National Institute of General Medical Sciences: $199,534.00
  • National Institute of General Medical Sciences: $224,444.00
  • National Institute of General Medical Sciences: $205,520.00
  • National Institute of General Medical Sciences: $210,994.00
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences: $302,896.00
  • National Institute of General Medical Sciences: $193,720.00

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