title: Sustained activation of DNA damage response in irradiated apoptosis-resistant cells induces reversible senescence associated with mTOR downregulation and expression of stem cell markers.
abstract: Cells respond to genotoxic stress by activating the DNA damage response (DDR). When injury is severe or irreparable, cells induce apoptosis or cellular senescence to prevent transmission of the lesions to the daughter cells upon cell division. Resistance to apoptosis is a hallmark of cancer that challenges the efficacy of cancer therapy. In this work, the effects of ionizing radiation on apoptosis-resistant E1A + E1B transformed cells were investigated to ascertain whether the activation of cellular senescence could provide an alternative tumor suppressor mechanism. We show that irradiated cells arrest cell cycle at G 2/M phase and resume DNA replication in the absence of cell division followed by formation of giant polyploid cells. Permanent activation of DDR signaling due to impaired DNA repair results in the induction of cellular senescence in E1A + E1B cells. However, irradiated cells bypass senescence and restore the population by dividing cells, which have near normal size and ploidy and do not express senescence markers. Reversion of senescence and appearance of proliferating cells were associated with downregulation of mTOR, activation of autophagy, mitigation of DDR signaling, and expression of stem cell markers.
authors.affiliation: Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; Saint Petersburg State University; St. Petersburg, Russia.
authors.forename: Zhanna V
authors.initials: ZV
authors.lastname: Chitikova
authors.affiliation: Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; Saint Petersburg State University; St. Petersburg, Russia.
authors.forename: Serguei A
authors.initials: SA
authors.lastname: Gordeev
authors.affiliation: Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; Saint Petersburg State University; St. Petersburg, Russia.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Bykova
authors.affiliation: Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; Saint Petersburg State University; St. Petersburg, Russia.
authors.forename: Svetlana G
authors.initials: SG
authors.lastname: Zubova
authors.affiliation: Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; Saint Petersburg State University; St. Petersburg, Russia.
authors.forename: Valery A
authors.initials: VA
authors.lastname: Pospelov
authors.affiliation: Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; Saint Petersburg State University; St. Petersburg, Russia.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Pospelova
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics; D017501:Adenovirus E1B Proteins / Q000235:genetics; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D015536:Down-Regulation; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000528:radiation effects*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D015415:Biomarkers; D000071317:Nanog Homeobox Protein; C547030:Nanog protein, rat; D050814:Octamer Transcription Factor-3; D014157:Transcription Factors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: DNA damage response; DNA repair; apoptosis resistance; autophagy; mTOR; polyploidy; senescence reversion; stem cells markers