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

Abstract

Inappropriate survival signaling after DNA damage may facilitate clonal expansion of genetically compromised cells, and it is known that protein tyrosine phosphatase (PTP) 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 PTP inhibition bypassed cell cycle arrest and abrogated Cr(VI)-induced clonogenic lethality. Notably, PTP inhibition resulted in an increase in forward mutations at the HPRT locus, supporting the hypothesis that PTP 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 PTP 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 PTP inhibitor, sodium orthovanadate, for up to 24 hours, 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 hours. In sharp contrast, PTP 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.

A novel F‐box domain containing cyclin F like gene is required for maintaining the genome stability and survival of chicken primordial germ cells

“…53,71,72 In mammals, each F-box protein can target multiple substrates, allowing the core SCF scaffold, by using different F-box proteins, to target hundreds of substrates for degradation. 53,[74][75][76] In addition, the rate of spontaneous mutation on the HPRT locus was detected at a high level in cancer cells as well as in a cell line carrying mutations on the DNA repair pathway genes. This hypothesis was also supported by our further studies on the chicken cyclin F like knockdown PGCs.…”

“…Induced alteration (overexpression or knockdown) of several genes causing DNA damage were reported to cause spontaneous mutations on the HPRT locus also due to unbalance of dNTP pool. 53,[74][75][76] In addition, the rate of spontaneous mutation on the HPRT locus was detected at a high level in cancer cells as well as in a cell line carrying mutations on the DNA repair pathway genes. 77 In this study, the cyclin F like knockdown PGCs resulted in spontaneous mutations, including frequent deletions and transitions on the chicken HPRT locus also, and had a low proportion of S-phase cells, suggesting that aberrant DNA damage lead to a failure of DNA replication during the cell cycle.…”

“…This hypothesis was also supported by our further studies on the chicken cyclin F like knockdown PGCs. Induced alteration (overexpression or knockdown) of several genes causing DNA damage were reported to cause spontaneous mutations on the HPRT locus also due to unbalance of dNTP pool . In addition, the rate of spontaneous mutation on the HPRT locus was detected at a high level in cancer cells as well as in a cell line carrying mutations on the DNA repair pathway genes .…”

Impact of Carcinogenic Chromium on the Cellular Response to Proteotoxic Stress

“…Such extensive damage leads to genotoxic stress. While genotoxic stress leads to p53-induced apoptosis in normal cells, in malignant cells it is tolerated and subverted, giving rise to a mosaic of genomic mutations and karyotypic abnormalities in solid tumors [37,38,39].…”