RNA Splicing: A New Player in the DNA Damage Response

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. 1. Overview of the DNA Damage Response 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 recognized as a characteristic of most solid tumors and adult-onset leukaemias and is manifested as alterations in chromosome number and structure (chromosomal instability) and as changes to the structure of DNA, such as nucleotide substitutions, insertions, and deletions. To maintain genomic stability and to counteract DNA damage, cells have evolved a complex cellular response, called DNA damage response (DDR), which is coordinated by the DNA damage checkpoints [1, 2]. Somatic mutations in DDR genes have been found in several cancer types [3]. Indeed, on one hand, inactivation of the DDR favors the accumulation of mutations in proto-oncogenes increasing the risk of tumor development. On the other, since the anticancer activity of most chemotherapeutic drugs relies on the induction of DNA damage, alterations in the DDR also affect the tumor’s sensitivity to chemotherapy [4]. Conceptually the molecules that orchestrate the DDR can be functionally organized in sensors, mediators, transducers and effectors. Recognition of DNA damage is the first step in the activation of the signaling cascade that controls the DNA damage checkpoints. DNA lesions are recognized by various sensor proteins: the MRN (MRE11-RAD50-NBS1) complex that signals double-strand DNA breaks (DBSs),