Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde
Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde
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DOI：
10.1158/0008-5472.can-07-3028
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发表时间：
2007-12-01
期刊：
影响因子：
11.2
通讯作者：
Nakamura, Jun
中科院分区：
文献类型：
--
作者：
Ridpath, John R.;Nakamura, Ayumi;Nakamura, Jun
甲醛是一种脂肪族单醛，是一种高活性的环境致癌物。虽然人类持续暴露于外源性甲醛，但这种活性醛是一种天然存在的生物化合物，存在于人类血浆中，浓度范围为13至97 μ mol/L。dna -蛋白质交联（DPC）可能在甲醛的遗传毒性和致癌性方面发挥重要作用。然而，对于哪些DNA损伤反应途径是细胞中和甲醛所必需的，我们知之甚少。在本研究中，我们首先使用多种DNA修复基因靶向突变的鸡DT40细胞评估了DNA损伤对血浆甲醛水平的反应。在这里，我们发现在缺乏BRCA/FANC途径、同源重组或翻译DNA合成的DT40突变体中检测到对甲醛的超敏反应。此外，fancd2缺陷的DT40细胞对乙醛过敏，但对丙烯醛、巴豆醛、乙二醛和甲基乙二醛不敏感。缺乏FANCC和FANCG的人类细胞也对血浆甲醛水平敏感。这些结果表明，BRCA/FANC通路对于抵消脂肪族单醛引起的DPCs至关重要。基于本研究获得的结果，我们目前提出内源性甲醛可能对高度增殖的细胞（如骨髓细胞）产生影响，并可能是范可尼贫血患者癌症的病因。
Formaldehyde is an aliphatic monoaldehyde and is a highly reactive environmental human carcinogen. Whereas humans are continuously exposed to exogenous formaldehyde, this reactive aldehyde is a naturally occurring biological compound that is present in human plasma at concentrations ranging from 13 to 97 mu mol/L. It has been well documented that DNA-protein crosslinks (DPC) likely play an important role with regard to the genotoxicity and carcinogenicity of formaldehyde. However, little is known about which DNA damage response pathways are essential for cells to counteract formaldehyde. In the present study, we first assessed the DNA damage response to plasma levels of formaldehyde using chicken DT40 cells with targeted mutations in various DNA repair genes. Here, we show that the hypersensitivity to formaldehyde is detected in DT40 mutants deficient in the BRCA/FANC pathway, homologous recombination, or translesion DNA synthesis. In addition, FANCD2-deficient DT40 cells are hypersensitive to acetaldehyde, but not to acrolein, crotonaldehyde, glyoxal, and methylglyoxal. Human cells deficient in FANCC and FANCG are also hypersensitive to plasma levels of formaldehyde. These results indicate that the BRCA/FANC pathway is essential to counteract DPCs caused by aliphatic monoaldehydes. Based on the results obtained in the present study, we are currently proposing that endogenous formaldehyde might have an effect on highly proliferating cells, such as bone marrow cells, as well as an etiology of cancer in Fanconi anemia patients.