Role of Pseudoexons and Pseudointrons in Human Cancer

In all eukaryotic organisms, pre-mRNA splicing and alternative splicing processes play an essential role in regulating the flow of information required to drive complex developmental and metabolic pathways. As a result, eukaryotic cells have developed a very efficient macromolecular machinery, called the spliceosome, to correctly recognize the pre-mRNA sequences that need to be inserted in a mature mRNA (exons) from those that should be removed (introns). In healthy individuals, alternative and constitutive splicing processes function with a high degree of precision and fidelity in order to ensure the correct working of this machinery. In recent years, however, medical research has shown that alterations at the splicing level play an increasingly important role in many human hereditary diseases, neurodegenerative processes, and especially in cancer origin and progression. In this minireview, we will focus on several genes whose association with cancer has been well established in previous studies, such as ATM, BRCA1/A2, and NF1. In particular, our objective will be to provide an overview of the known mechanisms underlying activation/repression of pseudoexons and pseudointrons; the possible utilization of these events as biomarkers of tumor staging/grading; and finally, the treatment options for reversing pathologic splicing events. 1. Introduction Starting from the first description of alternative splicing and constitutive splicing processes in 1977 [1–3], the importance of this process that guarantees the correct flow of information from transcription to translation in eukaryotic cells has continued to grow exponentially. In particular, one major branch of research in this area has the aim to investigate and characterize the cellular macromolecular machine (i.e., the spliceosome) that is physically responsible for the cutting and joining of intronsexons by catalyzing two transesterification reactions [4, 5] and the mechanisms that ensure its fidelity [6]. As a result, research in spliceosome composition and functioning has been complemented by studies aiming to understand the sequences and molecules that determine under which conditions a particular exon or intron is selectively recognized and included in the mature transcript. Therefore, after the basic elements that define introns and exons and are composed by donor and acceptor splice sites plus the branch point sequence, there was the discovery of enhancer and silencer elements that can affect either positively or negatively the way these basic elements are recognized by the spliceosome [7–9].