title: DNA repair in human pluripotent stem cells is distinct from that in non-pluripotent human cells.
abstract: The potential for human disease treatment using human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells (iPSCs), also carries the risk of added genomic instability. Genomic instability is most often linked to DNA repair deficiencies, which indicates that screening/characterization of possible repair deficiencies in pluripotent human stem cells should be a necessary step prior to their clinical and research use. In this study, a comparison of DNA repair pathways in pluripotent cells, as compared to those in non-pluripotent cells, demonstrated that DNA repair capacities of pluripotent cell lines were more heterogeneous than those of differentiated lines examined and were generally greater. Although pluripotent cells had high DNA repair capacities for nucleotide excision repair, we show that ultraviolet radiation at low fluxes induced an apoptotic response in these cells, while differentiated cells lacked response to this stimulus, and note that pluripotent cells had a similar apoptotic response to alkylating agent damage. This sensitivity of pluripotent cells to damage is notable since viable pluripotent cells exhibit less ultraviolet light-induced DNA damage than do differentiated cells that receive the same flux. In addition, the importance of screening pluripotent cells for DNA repair defects was highlighted by an iPSC line that demonstrated a normal spectral karyotype, but showed both microsatellite instability and reduced DNA repair capacities in three out of four DNA repair pathways examined. Together, these results demonstrate a need to evaluate DNA repair capacities in pluripotent cell lines, in order to characterize their genomic stability, prior to their pre-clinical and clinical use.
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Li Z
authors.initials: LZ
authors.lastname: Luo
authors.forename: Sailesh
authors.initials: S
authors.lastname: Gopalakrishna-Pillai
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Nay
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Park
authors.forename: Steven E
authors.initials: SE
authors.lastname: Bates
authors.forename: Xianmin
authors.initials: X
authors.lastname: Zeng
authors.forename: Linda E
authors.initials: LE
authors.lastname: Iverson
authors.forename: Timothy R
authors.initials: TR
authors.lastname: O'Connor
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D017209:Apoptosis / Q000528:radiation effects; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D053842:Microsatellite Instability; D039904:Pluripotent Stem Cells / Q000378:metabolism* / Q000528:radiation effects; D011740:Pyrimidine Dimers / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013463:Sulfuric Acid Esters / Q000494:pharmacology; D014158:Transcription, Genetic / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D000477:Alkylating Agents; D011740:Pyrimidine Dimers; D017382:Reactive Oxygen Species; D013463:Sulfuric Acid Esters; C007482:dimethyl sulfate