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

Zampetidis, C.; Galanos, P.; Angelopoulou, A.; Zhu, Y.; Karamitros, T.; Lagopati, N.; Mirzazadeh, R.; Polyzos, A.; Garnerone, S.; Gusmao, E. G.; Sofiadis, K.; Pefani, D. E.; Demaria, M.; Crosetto, N.; Maya-Mendoza, A.; Evangelou, K.; Bartek, J.; Papantonis, A.; Gorgoulis, V. G.

doi:10.1101/2020.12.20.423639

bioRxiv · 10.1101/2020.12.20.423639

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

Zampetidis, C.·Galanos, P.·Angelopoulou, A.·Zhu, Y.·Karamitros, T.·Lagopati, N.·Mirzazadeh, R.·Polyzos, A.·Garnerone, S.·Gusmao, E. G.·Sofiadis, K.·Pefani, D. E.·Demaria, M.·Crosetto, N.·Maya-Mendoza, A.·Evangelou, K.·Bartek, J.·Papantonis, A.·Gorgoulis, V. G.

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Abstract

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. HIGHLIGHTSO_LIOncogene driven error-prone repair produces early genetic lesions allowing escape from senescence C_LIO_LICells escaping oncogene-induced senescence display mutational signatures observed in cancer patients C_LIO_LIA single recurrent inversion harboring a circadian TF gene suffices for bypassing oncogene-induced senescence C_LIO_LIChromatin loop and compartment remodeling support the "escape" transcriptional program C_LI

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Zampetidis, C., Galanos, P., Angelopoulou, A., Zhu, Y., Karamitros, T., Lagopati, N., Mirzazadeh, R., Polyzos, A., Garnerone, S., Gusmao, E. G., Sofiadis, K., Pefani, D. E., Demaria, M., Crosetto, N., Maya-Mendoza, A., Evangelou, K., Bartek, J., Papantonis, A., Gorgoulis, V. G.. 2020-12-20. Genomic instability is an early event driving chromatin reorganization and escape from oncogene-induced senescence. https://doi.org/10.1101/2020.12.20.423639

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