Inhibition of activated pericentromeric SINE/Alu repeat transcription in senescent human adult stem cells reinstates self-renewal

Jianrong Wang, Glenn J. Geesman, Sirkka Liisa Hostikka, Michelle Atallah, Benjamin Blackwell, Elbert Lee, Peter J. Cook, Bogdan Pasaniuc, Goli Shariat, Eran Halperin, Marek Dobke, Michael G. Rosenfeld, I. King Jordan, Victoria V. Lunyak

Research output: Contribution to journalArticlepeer-review

Abstract

Cellular aging is linked to deficiencies in efficient repair of DNA double strand breaks and authentic genome maintenance at the chromatin level. Aging poses a significant threat to adult stem cell function by triggering persistent DNA damage and ultimately cellular senescence. Senescence is often considered to be an irreversible process. Moreover, critical genomic regions engaged in persistent DNA damage accumulation are unknown. Here we report that 65% of naturally occurring repairable DNA damage in self-renewing adult stem cells occurs within transposable elements. Upregulation of Alu retrotransposon transcription upon ex vivo aging causes nuclear cytotoxicity associated with the formation of persistent DNA damage foci and loss of efficient DNA repair in pericentric chromatin. This occurs due to a failure to recruit of condensin I and cohesin complexes. Our results demonstrate that the cytotoxicity of induced Alu repeats is functionally relevant for the human adult stem cell aging. Stable suppression of Alu transcription can reverse the senescent phenotype, reinstating the cells' self-renewing properties and increasing their plasticity by altering so-called "master" pluripotency regulators.

Original languageEnglish
Pages (from-to)3016-3030
Number of pages15
JournalCell Cycle
Volume10
Issue number17
DOIs
StatePublished - 1 Sep 2011

Keywords

  • Adult stem cells
  • ChIP-seq
  • Cohesin
  • Condensin
  • DNA damage
  • H2AX
  • Induced pluripotency
  • PML body
  • SINE/Alu transposons
  • Senescence

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