DNA damage regulation of the RNA components of the translational apparatus: New biology and mechanisms

It was shown more than 30 years ago that expression of ribosomal (r) RNAs processed from the large precursor rRNA is repressed when eukaryotic cells are exposed to genotoxic stress. More recently it has been found that other RNA components of the translational machinery, the tRNAs and 5S rRNA transcribed by RNA polymerase (pol) III, are also downregulated in cells that have experienced DNA damage. In other words, the DNA damage response involves coordinate repression of genes whose products comprise the heart of the translational machinery. This repression could be due to blockage of polymerase elongation, and indeed this mechanism was originally invoked to explain repression of pol I-transcribed rRNAs under conditions of genotoxic stress. Recent work however reveals the existence of a DNA damage signaling pathway that directly contributes to downregulation of the pol III and probably the pol I transcription initiation machinery. This pathway involves a highly conserved protein kinase, CK2. Its likely target is the TATA Binding Protein, which in most eukaryotes is required for transcription by both pol I and pol III. Here I consider the implications of these findings for our understanding of the physiology of the DNA damage response, and for the prospect of developing a comprehensive molecular model of how cells cope with genotoxic stress.