Source: http://www.asmscience.org/content/book/10.1128/9781555816704.ch22
Timestamp: 2019-04-21 02:36:56+00:00

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This chapter discusses the regulation of eukaryotic genes in response to DNA-damaging agents. The yeast Saccharomyces cerevisiae has been fruitfully used as a model organism to explore pathways of regulation of eukaryotic gene expression in response to DNA damage. The transcriptional responses of S. cerevisiae to DNA damaging agents are discussed in considerable detail to highlight, in a simple model system, the experimental approaches, concepts, and open questions encountered when multicellular eukaryotes are considered. Mammalian genes that are activated at the transcriptional level in response to treatment with DNA-damaging agents include some that are involved in DNA repair and repair-associated processes. However, many also encode transcription factors, secreted growth factors and growth factor receptors, protective cytoplasmic enzymes, and proteins normally associated with tissue injury and inflammation. Several of these are known or suspected proto-oncogenes. Compilations of vertebrate genes inducible by DNA-damaging agents that were characterized prior to 1995 can be found in the literature. Although now incomplete and supplemented by gene array studies, those lists still usefully illustrate the wide variety of DNA damage-responsive genes. Delineating a defined number of regulons in multicellular eukaryotes is even less feasible than in yeast. The chapter discusses some selected observations and concentrates on the elucidation of mechanisms and pathways wherever possible, and also focuses on the effects of UV radiation and IR.
Transcriptional control of RNR gene expression in S. cerevisiae. In response to DNA damage or replicational stress (Pol2 inhibition), checkpoint kinases Mec1, Rad53, and Dun1 are activated and phosphorylate the Crt1 repressor, which loses affinity for its binding sequence. The signal transduction pathway originates from DNA structure sensors such as the 9-1-1 complex (formed in S. cerevisiae from the proteins Ddc1, Rad17, and Mec3). In S phase, these sensors may be replaced by DNA polymerase ε (Pol2).
A cascade of protein kinases and other activators originating from the cell membrane results in activation of the transcription factors AP-1 following UV radiation. Note that transcription of JUN is activated by an AP-1-like transcription factor containing ATF-2 and JUN itself.
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