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Suppression of p53 and p21CIP1/WAF1 reduces arsenite-induced aneuploidy

Ana María Salazar1, Heather L Miller, Samuel C McNeely

  • 1Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico, D.F., Mexico.

Chemical Research in Toxicology
|December 17, 2009
PubMed

Insights

This study reveals that the DNA damage response proteins p53 and p21(CIP1/WAF1) are crucial in preventing aneuploidy, a common feature in human tumors. Their suppression increases chromosomal instability, impacting cancer development.

Area of Science:

  • Cell Biology
  • Genetics
  • Cancer Research

Background:

  • Aneuploidy and chromosomal rearrangements are hallmarks of human tumors.
  • The roles of p53 and p21(CIP1/WAF1) in chromosomal instability are not fully understood.

Purpose of the Study:

  • To investigate the involvement of p53 and p21(CIP1/WAF1) in aneugenesis and clastogenesis.
  • To determine the impact of environmental carcinogens on chromosomal integrity in the presence and absence of these proteins.

Main Methods:

  • Utilized siRNA to suppress p53 and p21(CIP1/WAF1) in human fibroblasts.
  • Exposed cells to sodium arsenite and assessed micronuclei (MN) formation using the cytokinesis-block assay.
  • Employed fluorescent in situ hybridization with a centromeric probe to distinguish between chromosomal fragments and whole chromosome missegregation.

Main Results:

  • Sodium arsenite induced aneuploidy (chromosome missegregation) in human fibroblasts.
  • Suppression of p53 or p21(CIP1/WAF1) reduced the incidence of arsenite-induced aneuploidy.
  • Cells lacking p53 function showed increased apoptosis upon mitotic arrest, preventing aneuploid cell formation.

Conclusions:

  • p53 and p21(CIP1/WAF1) play critical roles in preventing aneuploidy during exposure to genotoxic agents.
  • p53 deficiency leads to apoptosis, inhibiting the survival of aneuploid cells.
  • p21(CIP1/WAF1) appears to be involved in mitotic exit, a process necessary for aneuploid cells to persist.

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