Protein tyrosine phosphatase (PTP) inhibition enhances chromosomal stability after genotoxic stress: Decreased chromosomal instability (CIN) at the expense of enhanced genomic instability (GIN)?

作者：Kost Gina Chun; Patierno Steven R; Wise Sandra S; Holmes Amie L; Wise John Pierce Sr; Ceryak Susan^*

来源：Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis, 2012, 735(1-2): 51-55.

DOI：10.1016/j.mrfmmm.2012.05.001

• Chromosomal stability
• Mutagenesis
• PTP inhibition
• Cr(VI)

Inappropriate survival signaling after DNA damage may facilitate clonal expansion of genetically compromised cells, and it is known that protein tyrosine phosphatase (PIP) inhibitors activate key survival pathways. In this study we employed the genotoxicant, hexavalent chromium [Cr(VI)], which is a well-documented carcinogen of occupational and environmental concern. Cr(VI) induces a complex array of DNA damage, including DNA double strand breaks (DSBs). We recently reported that PIP inhibition bypassed cell cycle arrest and abrogated Cr(VI)-induced clonogenic lethality. Notably. PIP inhibition resulted in an increase in forward mutations at the HPRT locus, supporting the hypothesis that PIP inhibition in the presence of DNA damage may lead to genomic instability (GIN), via cell cycle checkpoint bypass. The aim of the present study was to determine the effect of PIP inhibition on DNA DSB formation and chromosomal integrity after Cr(VI) exposure. Diploid human lung fibroblasts were treated with Cr(VI) in the presence or absence of the PIP inhibitor, sodium orthovanadate, for up to 24 h, and cells were analyzed for DNA DSBs and chromosomal damage. Cr(VI) treatment induced a rapid increase in DNA DSBs, and a significant increase in total chromosomal damage (chromatid breaks and gaps) after 24 h. In sharp contrast, PIP inhibition abrogated both DNA DSBs and chromosomal damage after Cr(VI) treatment. In summary, PTP inhibition in the face of Cr(VI) genotoxic stress decreases chromosomal instability (CIN) but increases mutagenesis, which we postulate to be a result of error-prone DNA repair.

• 出版日期2012-7-1