Reduced expression of GINS complex members induces hallmarks of pre-malignancy in primary untransformed human cells

Laura R. Barkley, Young Song Ihn, Ying Zou, Cyrus Vaziri

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


In cancer cells ablation of the GINS complex member Psf2 elicits chromosome mis-segregation yet the precise role of Psf2 in mitosis is unknown. We investigated the putative mitotic role of the GINS complex using synchronized cultures of untransformed Human Dermal Fibroblasts (HDF). Metaphase spreads from Psf1/Psf2-depleted HDF were normal and mitotic exit of Psf1/Psf2-depleted cells was only slightly delayed, suggesting no direct role for the GINS complex in mitosis of untransformed cells. Because the GINS complex is required for initiation and elongation events during DNA replication we hypothesized that the mitotic delay of Psf1/Psf2-deficient cells resulted indirectly from defective DNA synthesis during a prior S-phase. Therefore, we investigated the effects of Psf1/Psf2-depletion on DNA replication. Recruitment of Mcm7 to chromatin during G1 was unaffected by Psf1/Psf2-ablation, indicating that replication licensing does not require GINS. However, chromatin-binding of Cdc45 and PCNA, onset of DNA synthesis and accumulation of G2/M markers were delayed in Psf1/Psf2-ablated cells. The cell cycle delay of Psf1/Psf2-depleted HDF was associated with several hallmarks of pre-malignancy including γH2AX, Thr 68-phosphorylated Chk2, and increased numbers of aberrant fragmented nuclei. Ectopic expression of catalytically-inactive Chk2 promoted S-phase and G 2/M progression in Psf1/Psf2-depleted cells, as evidenced by modestly-increased rates of DNA synthesis and increased dephosphorylation of Cdc2. Therefore, S-phase progression of untransformed cells containing sub-optimal levels of Psf1/2 is associated with replication stress and acquisition of DNA damage. The ensuing Chk2-mediated DNA damage signaling likely contributes to maintenance of chromosomal integrity.

Original languageEnglish (US)
Pages (from-to)1577-1588
Number of pages12
JournalCell Cycle
Issue number10
StatePublished - May 15 2009
Externally publishedYes


  • Cell cycle
  • Checkpoint signaling
  • DNA damage
  • DNA replication
  • Psf1
  • Psf2

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology


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