TY - JOUR T1 - Deletion of a pseudogene within a fragile site triggers the oncogenic expression of the mitotic CCSER1 gene JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202101019 VL - 4 IS - 8 SP - e202101019 AU - Benedetta M Santoliquido AU - Michela Frenquelli AU - Claudia Contadini AU - Stefano Bestetti AU - Marco Gaviraghi AU - Elisa Barbieri AU - Anna De Antoni AU - Luca Albarello AU - Angelo Amabile AU - Alessandro Gardini AU - Angelo Lombardo AU - Claudio Doglioni AU - Paolo Provero AU - Silvia Soddu AU - Davide Cittaro AU - Giovanni Tonon Y1 - 2021/08/01 UR - https://www.life-science-alliance.org/content/4/8/e202101019.abstract N2 - 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. ER -