title: Inhibition of activated pericentromeric SINE/Alu repeat transcription in senescent human adult stem cells reinstates self-renewal.
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.
authors.affiliation: School of Biology, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wang
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Geesman
authors.forename: Sirkka Liisa
authors.initials: SL
authors.lastname: Hostikka
authors.forename: Michelle
authors.initials: M
authors.lastname: Atallah
authors.forename: Benjamin
authors.initials: B
authors.lastname: Blackwell
authors.forename: Elbert
authors.initials: E
authors.lastname: Lee
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cook
authors.forename: Bogdan
authors.initials: B
authors.lastname: Pasaniuc
authors.forename: Goli
authors.initials: G
authors.lastname: Shariat
authors.forename: Eran
authors.initials: E
authors.lastname: Halperin
authors.forename: Marek
authors.initials: M
authors.lastname: Dobke
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: I King
authors.initials: IK
authors.lastname: Jordan
authors.forename: Victoria V
authors.initials: VV
authors.lastname: Lunyak
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism; D020087:Alu Elements; D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence; D002503:Centromere / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D002877:Chromosomes, Human / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006657:Histones / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D000097722:Cohesins
chemical_list: D000251:Adenosine Triphosphatases; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; D046912:Multiprotein Complexes; D000097722:Cohesins; C468783:H2AX protein, human; C108312:condensin complexes