Graduate program in Bioinformatics, Boston University, Boston, MA 02215, USA.
Nucleic Acids Res. 2012 Sep;40(16):7644-52. doi: 10.1093/nar/gks519. Epub 2012 Jun 16.
Formaldehyde has long been recognized as a hazardous environmental agent highly reactive with DNA. Recently, it has been realized that due to the activity of histone demethylation enzymes within the cell nucleus, formaldehyde is produced endogenously, in direct vicinity of genomic DNA. Should it lead to extensive DNA damage? We address this question with the aid of a computational mapping method, analogous to X-ray and nuclear magnetic resonance techniques for observing weakly specific interactions of small organic compounds with a macromolecule in order to establish important functional sites. We concentrate on the leading reaction of formaldehyde with free bases: hydroxymethylation of cytosine amino groups. Our results show that in B-DNA, cytosine amino groups are totally inaccessible for the formaldehyde attack. Then, we explore the effect of recently discovered transient flipping of Watson-Crick (WC) pairs into Hoogsteen (HG) pairs (HG breathing). Our results show that the HG base pair formation dramatically affects the accessibility for formaldehyde of cytosine amino nitrogens within WC base pairs adjacent to HG base pairs. The extensive literature on DNA interaction with formaldehyde is analyzed in light of the new findings. The obtained data emphasize the significance of DNA HG breathing.
甲醛长期以来一直被认为是一种环境危害物，它与 DNA 高度反应。最近，人们意识到由于细胞核内组蛋白去甲基化酶的活性，甲醛在基因组 DNA 的直接附近内源性产生。它会导致广泛的 DNA 损伤吗？我们借助于类似于 X 射线和核磁共振技术的计算映射方法来解决这个问题，这些技术用于观察小分子与大分子之间的弱特异性相互作用，以确定重要的功能位点。我们专注于甲醛与游离碱基的主要反应：胞嘧啶氨基羟甲基化。我们的结果表明，在 B-DNA 中，甲醛攻击完全无法触及胞嘧啶氨基。然后，我们探索了最近发现的 Watson-Crick（WC）对瞬时翻转成 Hoogsteen（HG）对（HG 呼吸）的影响。我们的结果表明，HG 碱基对的形成极大地影响了与 HG 碱基对相邻的 WC 碱基对中胞嘧啶氨基氮的甲醛可及性。根据新发现，对 DNA 与甲醛相互作用的广泛文献进行了分析。获得的数据强调了 DNA HG 呼吸的重要性。
