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14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage

T A Chan1, H Hermeking, C Lengauer

  • 1The Johns Hopkins Oncology Center, Program in Human Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.

Nature
|October 19, 1999
PubMed

Insights

Inactivating the 14-3-3sigma protein prevents cancer cells from halting cell division after DNA damage. This leads to cell death, suggesting a role for 14-3-3sigma in maintaining the G2 checkpoint.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • 14-3-3Sigma is a protein involved in regulating cellular activity by binding phosphorylated proteins.
  • Its expression is linked to the p53 tumor suppressor gene and it is suggested to promote cell-cycle arrest after DNA damage.
  • Maintaining the G2 checkpoint is crucial for preventing genomic instability and cell death.

Purpose of the Study:

  • To investigate the role of 14-3-3sigma in maintaining the G2 cell-cycle checkpoint following DNA damage.
  • To understand the mechanism by which 14-3-3sigma deficiency leads to cell death.

Main Methods:

  • Generation of human somatic-cell knockouts using an improved approach.
  • Creation of human colorectal cancer cells with inactivated 14-3-3sigma alleles (14-3-3sigma-/-).
  • Analysis of cell-cycle progression and protein sequestration in response to DNA damage.

Main Results:

  • 14-3-3sigma-/- cells initially arrested in G2 phase after DNA damage but failed to maintain the arrest.
  • These cells underwent 'mitotic catastrophe,' dying as they entered mitosis.
  • Deficiency in 14-3-3sigma led to failure in sequestering key mitotic proteins like cyclin B1 and cdc2, preventing their nuclear entry.

Conclusions:

  • 14-3-3sigma is essential for maintaining the G2 checkpoint and preventing mitotic catastrophe after DNA damage.
  • The mechanism involves the sequestration of proteins that initiate mitosis.
  • These findings shed light on a critical pathway for preventing cell death and maintaining genomic integrity.

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