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

Christos P Zampetidis1, Panagiotis Galanos2, Andriani Angelopoulou1

  • 1Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece.

Molecular Cell
|November 18, 2021
PubMed

Insights

Oncogene-induced senescence (OIS) can be escaped by senescent cells, leading to malignant transformation. A chromosomal inversion activating BHLHE40 drives this escape via replication stress.

Area of Science:

  • Cellular senescence
  • Tumor suppression
  • Genomic instability

Background:

  • Oncogene-induced senescence (OIS) is a crucial tumor suppressor mechanism.
  • Senescent cells, if not cleared, can promote detrimental effects, including malignant transformation.
  • The "escape" from senescence, distinct from the senescence-associated secretory phenotype (SASP), is an understudied unfavorable outcome.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying "escape" from oncogene-induced senescence.
  • To identify genetic alterations driving cell cycle re-entry and malignant transformation of senescent cells.

Main Methods:

  • Utilized a human epithelial cell model with an inducible CDC6 oncogene.
  • Analyzed genomic and functional data to identify chromosomal aberrations.
  • Investigated the role of the circadian transcription factor BHLHE40 in senescence escape.

Main Results:

  • Identified an early-acquired, recurrent chromosomal inversion upon CDC6 induction.
  • This inversion activates the BHLHE40 locus, driving cell cycle re-entry and malignant transformation.
  • Ectopic BHLHE40 expression inhibited CDC6-induced senescence; replication stress-induced genomic instability underlies senescence escape.

Conclusions:

  • A specific chromosomal inversion activating BHLHE40 is a key driver of "escape" from OIS.
  • Replication stress-induced genomic instability is implicated in the mechanism of senescence escape.
  • Understanding this escape pathway is critical for cancer prevention and therapy.
Keywords:
BHLHE40DNA damageDNA replicationHi-Ccancerchromatin loopreplication stresssenescence

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