Abstract
It is widely accepted that tumorigenesis is a multistep process characterized by the sequential accumulation of genetic alterations. However, the molecular basis of genomic instability in cancer is still partially understood. The observation that hereditary cancers are often characterized by mutations in DNA repair and checkpoint genes suggests that accumulation of DNA damage is a major contributor to the oncogenic transformation. It is therefore of great interest to identify all the cellular pathways that contribute to the response to DNA damage. Recently, RNA processing has emerged as a novel pathway that may contribute to the maintenance of genome stability. In this review, we illustrate several different mechanisms through which pre-mRNA splicing and genomic stability can influence each other. We specifically focus on the role of splicing factors in the DNA damage response and describe how, in turn, activation of the DDR can influence the activity of splicing factors.
Highlights
Genomic instability is one of the most common characteristics of tumor cells and is probably due to the combined effect of DNA damage, tumor-specific DNA repair defects, and a failure to arrest the cell cycle before the damaged DNA is passed on to daughter cells
Genomic instability is a hallmark of cancer cells, and the understanding of the mechanisms able to limit or counteract it can positively impact on the therapy of tumors
Genomewide approaches have revealed that genes involved in RNA processing are often deregulated in response to genotoxic treatments
Summary
Genomic instability is one of the most common characteristics of tumor cells and is probably due to the combined effect of DNA damage, tumor-specific DNA repair defects, and a failure to arrest the cell cycle before the damaged DNA is passed on to daughter cells. Different genotoxic treatments such as camptothecin, doxorubicin, and cisplatin induce MDM2 exon skipping by disrupting the interaction between EWS, a transcriptional coregulator [58], and the splicing factor YB1 [56] These results suggest that DNA damage may interfere with the coupling between transcription and splicing leading to the production of alternative or aberrant mRNA variants. These promoters have p53 binding elements at or near the start site suggesting that the protein isoforms encoded by these mRNA variants may have an active role in regulating the response to IR [59] These reports suggest that genotoxic damage can interfere with RNA polymerase II activity and may influence cotranscriptional AS by distinct mechanisms. Considering that the functional categories associated with the affected genes are related to crucial cellular programs one can speculate that these changes might be functionally relevant for the response to DNA damage
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