Inhibition of Activated Pericentromeric SINE/Alu Repeat Transcription in Senescent Human Adult Stem Cells Reinstates Self-Renewal

TitleInhibition of Activated Pericentromeric SINE/Alu Repeat Transcription in Senescent Human Adult Stem Cells Reinstates Self-Renewal
Publication TypeJournal Article
Year of Publication2011
AuthorsWang J, Geesman GJ, Hostikka SLiisa, Atallah M, Blackwell B, Lee E, Cook PJ, Pasaniuc B, Shariat G, Halperin E, Dobke M, Rosenfeld MG, I. Jordan K, Lunyak VV
Published inCell Cycle
Volume10
Issue17
Page(s)3016-3030
Other Numbers3193
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.

Acknowledgment

We thank Jeri Jenkins for help with manuscript preparation,Max Sarrazin for help with figures, and ABI Life Technologiesfor reagents and technical assistance for SOLiD instrumentation.For critical reading of the manuscript we are grateful toDrs. B. Kennedy, G. Lithgow and M. Classon. We thank Dr.Denise Muñoz and Justin Winstead for assistance with librarypreparation and sequencing runs. This work was supported byNational Institutes of Health pilot projects on UL1 DE019608,Buck Institute Trust Fund to V.V.L. and by the Alfred P. SloanFoundation (BR-4839) to I.K.J. V.V.L. designed the experiments;J.W. and I.K.J. developed and applied bioinformatics method fordata analysis; G.G., S.L.H., M.A., B.B. and E.L.L. performedthe experiments; P.J.C. and M.D. provided the primary cells;B.P. and E.H. mapped the SOLiD data, G.S. provided technicalassistance for SOLiD instrumentation; I.K.J., M.G.R. and V.V.L.discussed the results and wrote the paper.

URLhttp://www.icsi.berkeley.edu/pubs/algorithms/wangcellcycle11.pdf
Bibliographic Notes

Cell Cycle, Vol. 10, No.17, pp. 3016-3030

Abbreviated Authors

Jianrong Wang, G. J. Geesman, S. L. Hostikka, M. Atallah, B. Blackwell, E. Lee, P. J. Cook, B. Pasaniuc, G. Shariat, E. Halperin, M. Dobke, M. G. Rosenfeld, I. K. Jordan, and V. V. Lunyak

ICSI Research Group

Algorithms

ICSI Publication Type

Article in journal or magazine