title: Spontaneous Single-Copy Loss of TP53 in Human Embryonic Stem Cells Markedly Increases Cell Proliferation and Survival.
abstract: Genomic aberrations have been identified in many human pluripotent stem cell (hPSC) cultures. Commonly observed duplications in portions of chromosomes 12p and 17q have been associated with increases in genetic instability and resistance to apoptosis, respectively. However, the phenotypic consequences related to sporadic mutations have not been evaluated to date. Here, we report on the effects of a single-copy deletion of the chr17p13.1 region, a sporadic mutation that spontaneously arose independently in several subclones of a human embryonic stem cell culture. Compared to cells with two normal copies of chr17p13.1 ("wild-type"), the cells with a single-copy deletion of this region ("mutant") displayed a selective advantage when exposed to stressful conditions, and retained a higher percentage of cells expressing the pluripotency marker POU5F1/OCT4 after 2 weeks of in vitro differentiation. Knockdown of TP53, which is a gene encompassed by the deleted region, in wild-type cells mimicked the chr17p13.1 deletion phenotype. Thus, sporadic mutations in hPSCs can have phenotypic effects that may impact their utility for clinical applications. Stem Cells 2017;35:872-885.
authors.affiliation: Department of Reproductive Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Hadar
authors.initials: H
authors.lastname: Amir
authors.affiliation: Department of Reproductive Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Touboul
authors.affiliation: Department of Reproductive Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Sabatini
authors.affiliation: Department of Reproductive Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Chhabra
authors.affiliation: Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Ibon
authors.initials: I
authors.lastname: Garitaonandia
authors.affiliation: Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Jeanne F
authors.initials: JF
authors.lastname: Loring
authors.affiliation: Department of Reproductive Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Morey
authors.affiliation: Department of Reproductive Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Laurent
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002999:Clone Cells; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D018628:Gene Dosage; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D000066449:Human Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D019311:Staurosporine
keywords: Chromosomal aberrations; DNA repair; Embryonic stem cells; Proliferation; p53