Περίληψη:
Oncogene-induced senescence (OIS) is an inherent and important tumor
suppressor mechanism. However, if not removed timely via immune
surveillance, senescent cells also have detrimental effects. 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 is another unfavorable outcome. The mechanism
underlying this phenomenon remains elusive. 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 that harbors a locus encoding the circadian
transcription factor BHLHE40. This inversion alone suffices for BHLHE40
activation upon CDC6 induction and driving cell cycle re-entry of
senescent cells, and malignant transformation. Ectopic overexpression of
BHLHE40 prevented induction of CDC6-triggered senescence. We provide
strong evidence in support of replication stress-induced genomic
instability being a causative factor underlying “escape” from
oncogene-induced senescence.
Συγγραφείς:
Zampetidis, Christos P.
Galanos, Panagiotis
Angelopoulou,
Andriani
Zhu, Yajie
Polyzou, Aikaterini
Karamitros,
Timokratis
Kotsinas, Athanassios
Lagopati, Nefeli
Mourkioti,
Ioanna
Mirzazadeh, Reza
Polyzos, Alexandros
Garnerone,
Silvano
Mizi, Athanasia
Gusmao, Eduardo G.
Sofiadis,
Konstantinos
Gal, Zita
Larsen, Dorthe H.
Pefani,
Dafni-Eleftheria
Demaria, Marco
Tsirigos, Aristotelis and
Crosetto, Nicola
Maya-Mendoza, Apolinar
Papaspyropoulos, Angelos
and Evangelou, Konstantinos
Bartek, Jiri
Papantonis, Argyris and
Gorgoulis, Vassilis G.
