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

Mol Cell. 2021 Dec 2;81(23):4907-4923.e8. doi: 10.1016/j.molcel.2021.10.017. Epub 2021 Nov 17.


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.

Keywords: BHLHE40; DNA damage; DNA replication; Hi-C; cancer; chromatin loop; replication stress; senescence.

MeSH terms

  • Animals
  • Bronchi / metabolism
  • CRISPR-Cas Systems
  • Cell Cycle
  • Cell Transformation, Neoplastic
  • Cellular Senescence*
  • Chromosome Inversion*
  • Chromosomes / ultrastructure*
  • Circadian Rhythm
  • Computational Biology
  • Epithelial Cells / metabolism
  • Epithelial-Mesenchymal Transition*
  • Flow Cytometry
  • Genomics
  • Humans
  • Karyotyping
  • Mice
  • Mice, SCID
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Oncogenes*
  • Phenotype
  • Protein Binding
  • Protein Domains
  • Recombination, Genetic*
  • Senescence-Associated Secretory Phenotype