title: Genomic Instability in Human Pluripotent Stem Cells Arises from Replicative Stress and Chromosome Condensation Defects.
abstract: Human pluripotent stem cells (hPSCs) frequently acquire chromosomal aberrations such as aneuploidy in culture. These aberrations progressively increase over time and may compromise the properties and clinical utility of the cells. The underlying mechanisms that drive initial genomic instability and its continued progression are largely unknown. Here, we show that aneuploid hPSCs undergo DNA replication stress, resulting in defective chromosome condensation and segregation. Aneuploid hPSCs show altered levels of actin cytoskeletal genes controlled by the transcription factor SRF, and overexpression of SRF rescues impaired chromosome condensation and segregation defects in aneuploid hPSCs. Furthermore, SRF downregulation in diploid hPSCs induces replication stress and perturbed condensation similar to that seen in aneuploid cells. Together, these results suggest that decreased SRF expression induces replicative stress and chromosomal condensation defects that underlie the ongoing chromosomal instability seen in aneuploid hPSCs. A similar mechanism may also operate during initiation of instability in diploid cells.
authors.affiliation: Department of Genetics, The Hebrew University, Jerusalem, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Lamm
authors.affiliation: Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, The Hebrew University, Jerusalem, Israel; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Uri
authors.initials: U
authors.lastname: Ben-David
authors.affiliation: Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, The Hebrew University, Jerusalem, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Golan-Lev
authors.affiliation: A Group Maintenance of Genome Stability, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Storchová
authors.affiliation: Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, The Hebrew University, Jerusalem, Israel. Electronic address: nissimb@mail.huji.ac.il.
authors.forename: Nissim
authors.initials: N
authors.lastname: Benvenisty
authors.affiliation: Department of Genetics, The Hebrew University, Jerusalem, Israel. Electronic address: batshevak@savion.huji.ac.il.
authors.forename: Batsheva
authors.initials: B
authors.lastname: Kerem
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics; D000199:Actins / Q000378:metabolism; D000705:Anaphase; D000782:Aneuploidy; D002869:Chromosome Aberrations; D020090:Chromosome Segregation / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D004171:Diploidy; D015536:Down-Regulation / Q000235:genetics; D042822:Genomic Instability; D006801:Humans; D008677:Metaphase; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D000199:Actins; D026362:Serum Response Factor
keywords: SRF; aneuploidy; chromosomal aberrations; condensation perturbations; genomic instability; human pluripotent stem cells; replication stress