Induction of internucleosomal DNA fragmentation by carcinogenic chromate: relationship to DNA damage, genotoxicity, and inhibition of macromolecular synthesis.
Induction of internucleosomal DNA fragmentation by carcinogenic chromate: relationship to DNA damage, genotoxicity, and inhibition of macromolecular synthesis.
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DOI：
10.1289/ehp.94102s3159
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发表时间：
1994-09
影响因子：
10.4
通讯作者：
Patierno SR
中科院分区：
文献类型：
--
作者：
Manning FC;Blankenship LJ;Wise JP;Xu J;Bridgewater LC;Patierno SR
六价铬（Cr）化合物是人类和动物的呼吸道致癌物。用150和300 μ M铬酸钠（Na 2CrO 4）处理中国仓鼠卵巢细胞2小时，分别使集落形成效率降低46%和92%。这些治疗诱导剂量依赖性的细胞DNA的核小体间片段超过24小时后铬酸盐处理。这种断裂模式是细胞凋亡作为细胞死亡机制的特征。这些处理还诱导了大分子合成的立即抑制和细胞通过细胞周期的S期的延迟进展。细胞生长（如DNA合成所证明的）被抑制至少4天，转录保持抑制至少32小时。许多进展到中期的细胞表现出染色体损伤。铬酸盐引起的DNA单链断裂和DNA-蛋白质交联的剂量依赖性的形成，但这些修复后8和24小时去除的治疗，分别。相比之下，Cr-DNA加合物（高达1/100碱基对）对修复具有极强的抗性，即使在治疗后5天仍可检测到。与基因组的其他区域相比，DNA-蛋白质交联和Cr加合物优先与处理过的细胞的核基质DNA相关，其在活跃转录的基因中富集4.5倍。铬加合物，在体外形成的DNA在一个类似的水平，在核基质DNA中检测到的，逮捕了DNA聚合酶的进展，在序列特异性的方式，可能通过形成的DNA-DNA交联。（250字处删节）
Hexavalent chromium (Cr) compounds are respiratory carcinogens in humans and animals. Treatment of Chinese hamster ovary cells with 150 and 300 microM sodium chromate (Na2CrO4) for 2 hr decreased colony-forming efficiency by 46 and 92%, respectively. These treatments induced dose-dependent internucleosomal fragmentation of cellular DNA beyond 24 hr after chromate treatment. This fragmentation pattern is characteristic of apoptosis as a mechanism of cell death. These treatments also induced an immediate inhibition of macromolecular synthesis and delayed progression of cells through S-phase of the cell cycle. Cell growth (as evidenced by DNA synthesis) was inhibited for at least 4 days and transcription remained suppressed for at least 32 hr. Many of the cells that did progress to metaphase exhibited chromosome damage. Chromate caused the dose-dependent formation of DNA single-strand breaks and DNA-protein cross-links, but these were repaired 8 and 24 hr after removal of the treatment, respectively. In contrast, Cr-DNA adducts (up to 1/100 base-pairs) were extremely resistant to repair and were still detectable even 5 days after treatment. Compared with other regions of the genome, DNA-protein cross-links and Cr adducts were preferentially associated with the nuclear matrix DNA of treated cells, which was 4.5-fold enriched in actively transcribed genes. Chromium adducts, formed on DNA in vitro at a similar level to that detected in nuclear matrix DNA, arrested the progression of a DNA polymerase in a sequence-specific manner, possibly through the formation of DNA-DNA cross-links.(ABSTRACT TRUNCATED AT 250 WORDS)