Review The role of alternative mRNA splicing in chromosome instability Alejandro Lo ´ pez-Saavedra, Luis A. Herrera * Unidad de Investigacio ´n Biome ´dica en Ca ´ncer, Instituto de Investigaciones Biome ´dicas, Universidad Nacional Auto ´noma de Me ´xico, Instituto Nacional de Cancerologı´a, Mexico Contents 1. Introduction ..................................................................................................... 246 2. Cohesion defects ................................................................................................. 247 2.1. Transcriptional variants in cohesion ............................................................................ 247 3. MSC defects ..................................................................................................... 247 3.1. MSC transcriptional variants .................................................................................. 247 4. Multiple centrosomes ............................................................................................. 249 4.1. Transcriptional variants in the origin of multiple centrosomes ....................................................... 249 5. Final remarks .................................................................................................... 250 Acknowledgements ............................................................................................... 250 References ...................................................................................................... 250 1. Introduction Chromosomal instability (CIN) has been defined as the increased probability of acquiring chromosomal aberrations owing to defects in processes such as DNA repair, replication or chromosome segregation. CIN describes the rate (cell-to-cell variability) of loss or gain of complete or partial chromosomes, and it is believed to be an early event during carcinogenesis, thus it is involved in tumor initiation [1]. CIN is a general property of aneuploid cancer cells. Although CIN should not be considered as a synonymous of aneuploidy, in the majority of cases, aneuploidy is the result of an underlying CIN [2]. This loss and gain of chromosomes allow the occurrence of a microevolutionary process in which cells may acquire advantageous properties for develop- ment and survival. The loss of control of an orderly mitotic division is crucial for the progression of many types of cancer towards malignancy and resistance to chemotherapy [3]. The mechanisms that lead to CIN are varied and complex, these include defects in different processes, such as the cohesion of chromatids, the mitotic spindle checkpoint (MSC), the number of centrosomes, the dynamic of microtubules (MTs) attachment to the kinetochores, and regulation of the cell cycle [4]. All of these processes are controlled by a series of proteins that are briefly described here and that have been widely documented in literature. Studies regarding these proteins in cancer cell lines and cancerous tissues have focused on finding associations between mutations in the genes coding for them, or the levels of these proteins, with the degree of malignancy, CIN, and metastasis. However, only few studies have focused on the alternative protein products generated from the same messenger Mutation Research 705 (2010) 246–251 ARTICLE INFO Article history: Received 24 June 2010 Received in revised form 9 September 2010 Accepted 27 September 2010 Available online 20 October 2010 Keywords: Cancer Aneuploidy Chromosome instability Splicing ABSTRACT Chromosomal instability (CIN) involves the gain or loss of complete or partial chromosomes during cellular division, and it is a common characteristic of tumors that have aneuploidy. In addition, CIN is considered to be a closely related event to carcinogenesis. The mechanisms that lead to CIN include defects in the cohesion of sister chromatids, mitotic spindle checkpoint, and regulation of the number of centrosomes. Different studies have found that transcription variants, also known as isoforms, which are generated by the alternative splicing of exons and introns in mRNA that encodes many of the regulator proteins of chromosomal segregation, have an important role in mechanisms that lead to CIN. The majority of these isoforms are newly described. The discovery of additional isoforms and the study of their mechanisms of action allow a more integrated view of how cells regulate the segregation of their genetic material, and of how errors occur in chromosomal segregation. ß 2010 Elsevier B.V. All rights reserved. * Corresponding author at: Instituto de Investigaciones Biome ´ dicas, Universidad Nacional Auto ´ noma de Me ´ xico, P.O. Box 70-228, Ciudad Universitaria, Me ´ xico D.F. 04510, Mexico. E-mail address: herreram@biomedicas.unam.mx (L.A. Herrera). Contents lists available at ScienceDirect Mutation Research/Reviews in Mutation Research journal homepage: www.elsevier.com/locate/reviewsmr Community address: www.elsevier.com/locate/mutres 1383-5742/$ – see front matter ß 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.mrrev.2010.09.002