Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, OR 97239, USA.
DNA Repair (Amst). 2012 Mar 1;11(3):236-46. doi: 10.1016/j.dnarep.2011.11.001. Epub 2011 Dec 18.
Formaldehyde is a reactive chemical that is commonly used in the production of industrial, laboratory, household, and cosmetic products. The causal association between formaldehyde exposure and increased incidence of cancer led the International Agency for Research on Cancer to classify formaldehyde as a carcinogen. Formaldehyde-induced DNA-protein crosslinks (DPCs) elicit responses involving nucleotide excision repair (NER) and homologous recombination (HR) repair pathways; however, little is known about the cellular and genetic changes that subsequently lead to formaldehyde-induced genotoxic and cytotoxic effects. Herein, investigations of genes that modulate the cytotoxic effects of formaldehyde exposure revealed that of five NER-deficient Chinese Hamster Ovary (CHO) cell lines tested, XPF- and ERCC1-deficient cells were most sensitive to formaldehyde treatment as compared to wild-type cells. Cell cycle analyses revealed that formaldehyde-treated XPF-deficient cells exhibited an immediate G2/M arrest that was associated with altered cell ploidy and apoptosis. Additionally, an elevated number of DNA double-strand breaks (DSBs), chromosomal breaks and radial formation were also observed in XPF-deficient cells following formaldehyde treatment. Formaldehyde-induced DSBs occurred in a replication-dependent, but an XPF-independent manner. However, delayed DSB repair was observed in the absence of XPF function. Collectively, our findings highlight the role of an XPF-dependent pathway in mitigating the sensitivity to formaldehyde-induced DNA damage as evidenced by the increased genomic instability and reduced cell viability in an XPF-deficient background. In addition, centrosome and microtubule abnormalities, as well as enlarged nuclei, caused by formaldehyde exposure are demonstrated in a repair-proficient cell line.
甲醛是一种反应性化学物质，通常用于生产工业、实验室、家庭和化妆品产品。甲醛暴露与癌症发病率增加之间的因果关系导致国际癌症研究机构将甲醛归类为致癌物质。甲醛诱导的 DNA-蛋白质交联（DPC）引发涉及核苷酸切除修复（NER）和同源重组（HR）修复途径的反应；然而，对于随后导致甲醛诱导的遗传毒性和细胞毒性作用的细胞和遗传变化知之甚少。在此，研究了调节甲醛暴露细胞毒性作用的基因，发现在所测试的五个 NER 缺陷型中国仓鼠卵巢（CHO）细胞系中，与野生型细胞相比，XPF 和 ERCC1 缺陷细胞对甲醛处理最为敏感。细胞周期分析表明，甲醛处理的 XPF 缺陷细胞立即出现 G2/M 期阻滞，这与细胞倍性改变和细胞凋亡有关。此外，在 XPF 缺陷细胞中还观察到甲醛处理后 DNA 双链断裂（DSB）、染色体断裂和放射状形成的数量增加。甲醛诱导的 DSBs 以依赖复制但不依赖 XPF 的方式发生。然而，在 XPF 功能缺失的情况下，观察到 DSB 修复延迟。总之，我们的研究结果强调了 XPF 依赖性途径在减轻甲醛诱导的 DNA 损伤敏感性方面的作用，这表现在 XPF 缺陷背景下基因组不稳定性增加和细胞活力降低。此外，在修复功能良好的细胞系中，甲醛暴露会导致中心体和微管异常以及核增大。
