Novel genetic and epigenetic alterations in ... - Ous-research.no

Previous studies have shown that RCC2 (also known as TD-60) is associated with thesegregation of chromosomes in metaphase.[34] Indeed, RCC2 is critical for the integrationof kinetochores into the mitotic spindle, and may be required for overall spindleassembly.[35] siRNA suppression shows that RCC2 is absolutely required for progressionfrom prometaphase to metaphase and that its suppression activates the spindle assemblycheckpoint, hence creating an effective G2/M arrest, indefinitely blocking cells fromcompleting mitosis.[35] The same study also suggested that the presence of RCC2 is criticalfor the recruitment of other proteins involved in cell division to inner centromeres inmitosis, supported by a novel study which show that RCC2 is important for AURORA B (aprotein involved in the chromosomal passenger complex) localization, but not activity, andthat RCC2-depleted extracts were impaired in their ability to align chromosomes to themetaphase plate.[36]These findings support the assumption that mutation in RCC2 can be associated withimproved survival as cells with this mutation will be arrested before cell division if themutation causes transcriptional inactivation. The (A)10 repeat in RCC2 is located in exon 1which is in the 5’ untranslated region (UTR) of the gene, 76 bases upstream of the startcodon. UTRs are known to affect mRNA nuclear export, cytoplasmic localization andtranslational efficiency and stability.[37] The majority of translational control occurs at thelevel of initiation, thus implicating the 5’ UTR as a major site of translationalregulation.[38;39] It has also been shown that mononucleotide repeats in UTRs areconserved due to possible selective pressure relating to a functional role, and that theseconserved repeats are frequently altered in MSI-cancers, and so are speculated to be involvedin regulating gene expression.[40] Whether or not the indels seen in RCC2 arrest the cells22