Deletion of a pseudogene within a fragile site triggers the oncogenic expression of the mitotic CCSER1 gene
| Autor: | Elisa Barbieri, Claudio Doglioni, Silvia Soddu, Michela Frenquelli, Paolo Provero, Marco Gaviraghi, Stefano Bestetti, Giovanni Tonon, Claudia Contadini, Angelo Amabile, Angelo Lombardo, Alessandro Gardini, Luca Albarello, Davide Cittaro, Anna De Antoni, Benedetta Maria Santoliquido |
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| Přispěvatelé: | Santoliquido, B. M., Frenquelli, M., Contadini, C., Bestetti, S., Gaviraghi, M., Barbieri, E., de Antoni, A., Albarello, L., Amabile, A., Gardini, A., Lombardo, A., Doglioni, C., Provero, P., Soddu, S., Cittaro, D., Tonon, G. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Genome instability Health Toxicology and Mutagenesis Pseudogene Mitosis Cell Cycle Proteins Plant Science Biology Biochemistry Genetics and Molecular Biology (miscellaneous) Genomic Instability Cell Line 03 medical and health sciences 0302 clinical medicine Aurora kinase Gene silencing Humans Gene Research Articles Cell Proliferation Ecology CCSER1 Gene Chromosomal fragile site Chromosome Fragile Sites Up-Regulation Gene Expression Regulation Neoplastic 030104 developmental biology HEK293 Cells Centrosome 030220 oncology & carcinogenesis Cancer research Pseudogenes Gene Deletion Research Article HeLa Cells |
| Zdroj: | Life Science Alliance |
| Popis: | Frequent deletions impacting the FRA4F fragile site leads to the oncogenic overexpression of the corresponding CCSER1 gene, through the deletion of the TMSB4XP8 pseudogene. The ensuing CCSER1 overexpression elicits mitotic instability, targetable with aurora kinase inhibitors. The oncogenic role of common fragile sites (CFS), focal and pervasive gaps in the cancer genome arising from replicative stress, remains controversial. Exploiting the TCGA dataset, we found that in most CFS the genes residing within the associated focal deletions are down-regulated, including proteins involved in tumour immune recognition. In a subset of CFS, however, the residing genes are surprisingly overexpressed. Within the most frequent CFS in this group, FRA4F, which is deleted in up to 18% of cancer cases and harbours the CCSER1 gene, we identified a region which includes an intronic, antisense pseudogene, TMSB4XP8. TMSB4XP8 focal ablation or transcriptional silencing elicits the overexpression of CCSER1, through a cis-acting mechanism. CCSER1 overexpression increases proliferation and triggers centrosome amplifications, multinuclearity, and aberrant mitoses. Accordingly, FRA4F is associated in patient samples to mitotic genes deregulation and genomic instability. As a result, cells overexpressing CCSER1 become sensitive to the treatment with aurora kinase inhibitors. Our findings point to a novel tumourigenic mechanism where focal deletions increase the expression of a new class of “dormant” oncogenes. |
| Databáze: | OpenAIRE |
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