SUMMARY Oncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not timely removed via immune surveillance, senescent cells will also present a detrimental side. Although this has mostly been attributed to the senescence-associated-secretory-phenotype (SASP) of these cells, we recently proposed that “escape” from the senescent state represents another unfavorable outcome. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducible CDC6 oncogene to identify an early-acquired recurrent chromosomal inversion, which harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for BHLHE40 activation upon CDC6 induction and for driving cell cycle re-entry and malignant transformation. In summary, we now provide strong evidence in support of genomic instability underlying “escape” from oncogene-induced senescence. HIGHLIGHTS Oncogene driven error-prone repair produces early genetic lesions allowing escape from senescence Cells escaping oncogene-induced senescence display mutational signatures observed in cancer patients A single recurrent inversion harboring a circadian TF gene suffices for bypassing oncogene-induced senescence Chromatin loop and compartment remodeling support the “escape” transcriptional program

Genomic instability is an early event driving chromatin reorganization and escape from oncogene-induced senescence