[PDF][PDF] HuR in the mammalian genotoxic response: post-transcriptional multitasking

M Gorospe - Cell Cycle, 2003 - Taylor & Francis
Cell Cycle, 2003Taylor & Francis
DNA damage occurs in the cell through the action of endogenous agents such as reactive
oxidant intermediates and normal DNA metabolism, and also by exogenous factors such as
ultraviolet light (UV) and ionizing radiation. While different kinds of DNA lesions are repaired
by different sets of proteins, all types of DNA damage can trigger a series of events
collectively known as the DNA damage response. The mammalian DNA damage response
comprises several features: sensing the damage, triggering signal transduction cascades …
DNA damage occurs in the cell through the action of endogenous agents such as reactive oxidant intermediates and normal DNA metabolism, and also by exogenous factors such as ultraviolet light (UV) and ionizing radiation. While different kinds of DNA lesions are repaired by different sets of proteins, all types of DNA damage can trigger a series of events collectively known as the DNA damage response. The mammalian DNA damage response comprises several features: sensing the damage, triggering signal transduction cascades, activating checkpoints to slow down or arrest cell cycle progression, changing chromatin structure at the site of the damage, and altering gene expression patterns in the cell. 1 The newly implemented gene expression profiles will, in turn, dictate whether the cell will undergo transient or terminal growth inhibition, increase proliferation, enter senescence or trigger cell death. Intriguingly however, the presence of damaged DNA causes an inhibition of general transcription through mechanisms that include the hyperphosphorylation of RNA polymerase II, the diverting of transcription factor (TF) IIH away from transcription and into repair, and the sequestration of TATA-binding protein (TBP) onto damaged DNA (reviewed in ref. 2). The inhibition of transcription through these or other molecular events can vary depending on the type of genotoxin and the extent of the damage and is not relieved until the DNA is repaired. 2
How then does the cell implement gene expression changes to adequately sense the damage, repair macromolecules, and elicit a proper response? Several recent studies support the possibility that post-transcriptional gene regulatory events might be a leading mechanism of regulating gene expression in response to DNA damage. Our earlier work3 sets the stage for this model through the demonstration that post-transcriptional events, and mRNA turnover in particular, critically influenced mRNA steady-state levels in response to various stress agents. In the Fan et al. investigation, 3 cDNA arrays were used to evaluate the relative roles of gene transcription and mRNA turnover in governing gene expression changes. The analysis was based on the comparison of hybridization patterns acquired from newly transcribed RNA (obtained from nuclear run-on reactions) and from steady-state mRNA pools. According to these studies, mRNA turnover (stabilization as well as destabilization) accounted for approximately one half of the changes in mRNA steady-state levels following stress, while the other half was attributed primarily to altered transcription. 3 While this was the first systematic demonstration that stress-triggered gene expression in human cells is tightly linked to post-transcriptional regulation, other gene expression studies after genotoxic stress support these conclusions. Notably among them, exposure of human carcinoma cells to short wavelength UV light (UVC) was shown to stabilize the p21 mRNA, an effect linked to the association of the transcript with the RNA-binding protein HuR. 4 HuR is a ubiquitously expressed member of the Hu/ELAV (embryonic lethal abnormal vision in D. melanogaster) family of RNA-binding proteins, which also comprises the primarily neuronal proteins HuB, HuC, and HuD. 5-9 Hu proteins possess three RNA-recognition motifs through which they bind with high affinity and specificity to target mRNAs containing regions rich in adenines and uracils (AU-rich elements or AREs), and to regulate their stability (as shown for VEGF, p21, cyclin A, cyclin B1, c-fos), translation (as reported for p27, neurofilament N, GAP-43 and p53), or both (as reported for GLUT1). 10-18 Like other RNA …
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