Genomic Instability in Human Pluripotent Stem Cells Arises from Replicative Stress and Chromosome Condensation Defects

Noa Lamm, Uri Ben-David, Tamar Golan-Lev, Zuzana Storchová, Nissim Benvenisty*, Batsheva Kerem

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

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.

Original languageEnglish
Pages (from-to)253-261
Number of pages9
JournalCell Stem Cell
Volume18
Issue number2
DOIs
StatePublished - 4 Feb 2016
Externally publishedYes

Funding

FundersFunder number
Human Frontiers Science Program
Israeli Cancer Association
N.B. N.B.
Israel Cancer Research Fund
Rosetrees Trust269/12
Israel Science Foundation176/11
Azrieli Foundation
Israeli Centers for Research Excellence41/11
Office of the Chief Scientist, Ministry of Health

    Keywords

    • SRF
    • aneuploidy
    • chromosomal aberrations
    • condensation perturbations
    • genomic instability
    • human pluripotent stem cells
    • replication stress

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