Review The role of DNA repair in the pluripotency and differentiation of human stem cells Clarissa Ribeiro Reily Rocha a,1 , Leticia Koch Lerner a,1 , Oswaldo Keith Okamoto b , Maria Carolina Marchetto c , Carlos Frederico Martins Menck a, * a Department of Microbiology, Institute of Biomedical Sciences, University of Sa ˜o Paulo, Av. Prof. Lineu Prestes, 1374, Sa˜o Paulo, SP 05508 900, Brazil b Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sa˜o Paulo, Rua do Mata˜o, 277, Sa˜o Paulo, SP 05508-090, Brazil c Laboratory of Genetics (LOG-G), The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 2. Adult stem cells have elevated DNA repair capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 3. DNA damage response in stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4. Cancer stem cells: the dark side of DNA repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 5. The intimate relationships between DNA repair, stem cells and aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 6. Embryonic stem cells have the highest DNA repair capacity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 7. DNA repair efficiencies in induced pluripotent stem cells and in embryonic stem cells are equivalent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 7.1. Cellular therapy using iPS cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 7.2. iPS cell therapy for patients with DNA repair deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 7.3. Can a DNA repair deficient cell generate an iPS cell? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 8. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Mutation Research 752 (2013) 25–35 A R T I C L E I N F O Article history: Received 29 June 2012 Received in revised form 13 September 2012 Accepted 14 September 2012 Available online 23 September 2012 Keywords: DNA repair Embryonic stem cells Induced pluripotent stem cells (iPS) Reprogramming Cellular therapy A B S T R A C T All living cells utilize intricate DNA repair mechanisms to address numerous types of DNA lesions and to preserve genomic integrity, and pluripotent stem cells have specific needs due to their remarkable ability of self-renewal and differentiation into different functional cell types. Not surprisingly, human stem cells possess a highly efficient DNA repair network that becomes less efficient upon differentiation. Moreover, these cells also have an anaerobic metabolism, which reduces the mitochondria number and the likelihood of oxidative stress, which is highly related to genomic instability. If DNA lesions are not repaired, human stem cells easily undergo senescence, cell death or differentiation, as part of their DNA damage response, avoiding the propagation of stem cells carrying mutations and genomic alterations. Interestingly, cancer stem cells and typical stem cells share not only the differentiation potential but also their capacity to respond to DNA damage, with important implications for cancer therapy using genotoxic agents. On the other hand, the preservation of the adult stem cell pool, and the ability of cells to deal with DNA damage, is essential for normal development, reducing processes of neurodegeneration and premature aging, as one can observe on clinical phenotypes of many human genetic diseases with defects in DNA repair processes. Finally, several recent findings suggest that DNA repair also plays a fundamental role in maintaining the pluripotency and differentiation potential of embryonic stem cells, as well as that of induced pluripotent stem (iPS) cells. DNA repair processes also seem to be necessary for the reprogramming of human cells when iPS cells are produced. Thus, the understanding of how cultured pluripotent stem cells ensure the genetic stability are highly relevant for their safe therapeutic application, at the same time that cellular therapy is a hope for DNA repair deficient patients. ß 2012 Elsevier B.V. All rights reserved. * Corresponding author. Tel.: +55 11 3091 7499; fax: +55 11 3091 7354. E-mail address: cfmmenck@usp.br (C.F.M. Menck). 1 Both authors contributed equally to this work. Contents lists available at SciVerse ScienceDirect Mutation Research/Reviews in Mutation Research jo u rn al h om epag e: ww w.els evier.c o m/lo cat e/review sm r Co mm un ity ad dr es s: w ww.els evier .co m/lo c ate/mu tr es 1383-5742/$ – see front matter ß 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.mrrev.2012.09.001