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Transcriptional inhibition by carcinogenic chromate: Relationship to DNA damage
Author(s) -
Manning Francis C. R.,
Xu Jian,
Patierno Steven R.
Publication year - 1992
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.2940060409
Subject(s) - chromate conversion coating , biology , dna , carcinogen , microbiology and biotechnology , rna , dna damage , chromium , gene expression , messenger rna , transcription (linguistics) , gene , biochemistry , chemistry , linguistics , philosophy , organic chemistry
Hexavalent chromium compounds are carcinogenic to humans, are potent inducers of tumors in experimental animals, and can neoplastically transform cells in culture. In this study, the effects of sodium chromate on the expression of the 78‐kDa glucose‐regulated protein (GRP78) gene and on general transcription were investigated with respect to the DNA damage induced by this agent. DNA single‐strand breaks, DNA‐protein cross‐links, and chromium‐DNA adducts were present in CHO cells immediately after 2 h of treatment with sodium chromate. Subsequently, these types of damage were repaired at different rates. Single‐strand breaks were essentially repaired after 8 h. By 24 h posttreatment, no cross‐links remained in cells exposed to 30 or 150 μM chromate, although cells treated with the 300‐μM concentration still contained cross‐links at that time. DNA‐chromium adducts remained unrepaired for at least 32 h. The moderate constitutive level of GRP78 mRNA was not affected by chromate. Chromate did, however, suppress induction of this gene by tunicamycin in a concentration‐ and time‐dependent manner. Thirty micromolar sodium chromate (96% survival), which caused the least DNA damage, had no effect on GRP78 induction, general RNA synthesis, or mRNA synthesis. Induction of GRP78 was suppressed immediately and 12 h after treatment with 150 μM chromate (54% survival), although there was a partial recovery of induction at 24 h after treatment, which correlated with the repair of DNA‐protein cross‐links. In contrast, both total cytoplasmic RNA and mRNA synthesis were suppressed by approximately 60–75% for at least 32 h by 150 μM chromate. At the 300‐μM concentration (8% survival), where DNA‐protein cross‐links persisted beyond 24 h, GRP78 induction was totally suppressed for at least 24 h, while total RNA and mRNA synthesis were suppressed by 80–90% for at least 32 h. Overall, the effects of chromate on GRP78 induction correlated most closely with the presence of DNA‐protein cross‐links, but suppression of total RNA and mRNA synthesis correlated with the presence of DNA‐chromium adducts. These results indicate that chromate exerts differential effects on the induction of the GRP78 gene and on general transcription. © 1992 Wiley‐Liss, Inc.