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September 2022

A recurrent chromosomal inversion suffices for driving escape from oncogene-induced senescence via subTAD reorganization

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Christos P. Zampetidis, Panagiotis Galanos, Andriani Angelopoulou, Yajie Zhu, Aikaterini Polyzou, Timokratis Karamitros, Athanassios Kotsinas, Nefeli Lagopati, Ioanna Mourkioti, Reza Mirzazadeh, Alexandros Polyzos, Silvano Garnerone, Athanasia Mizi, Eduardo G. Gusmao, Konstantinos Sofiadis, Zita Gál, Dorthe H. Larsen, Dafni-Eleftheria Pefani, Vassilis G. Gorgoulis

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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.

The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice

Qixia Xu, Qiang Fu, Zi Li, Hanxin Liu, Ying Wang, Xu Lin, Ruikun He, Xuguang Zhang, Zhenyu Ju, Judith Campisi, James L. Kirkland & Yu Sun

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Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation of senescent cells, which develop the senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component of grape seed extract (GSE), increases the healthspan and lifespan of mice through its action on senescent cells. By screening a library of natural products, we find that GSE, and PCC1 as one of its active components, have specific effects on senescent cells. At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction. In rodent models, PCC1 depletes senescent cells in a treatment-damaged tumour microenvironment and enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration of PCC1 to either irradiated, senescent cell-implanted or naturally aged old mice alleviates physical dysfunction and prolongs survival. We identify PCC1 as a natural senotherapeutic agent with in vivo activity and high potential for further development as a clinical intervention to delay, alleviate or prevent age-related pathologies.