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Deletion of a pseudogene within a fragile site triggers the oncogenic expression of the mitotic CCSER1 gene

Authors :
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
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.
Source :
Life Science Alliance
Publication Year :
2021

Abstract

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.<br />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.

Details

Language :
English
Database :
OpenAIRE
Journal :
Life Science Alliance
Accession number :
edsair.doi.dedup.....3c17dd7f72c82eb111f775bdce7e1e87