Trerotola Marco, Antolini Laura, Beni Laura, Guerra Emanuela, Spadaccini Mariano, Verzulli Damiano, Moschella Antonino, Alberti Saverio
Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University "G. D' Annunzio", Via L. Polacchi 11, 66100 Chieti, Italy.
Center for Biostatistics, Department of Clinical Medicine, Prevention and Biotechnology, University of Milano-Bicocca, 20052 Monza, Italy.
NAR Genom Bioinform. 2022 Mar 4;4(1):lqac008. doi: 10.1093/nargab/lqac008. eCollection 2022 Mar.
The recognition code between transcription factor (TF) amino acids and DNA bases remains poorly understood. Here, the determinants of TF amino acid-DNA base binding selectivity were identified through the analysis of crystals of TF-DNA complexes. Selective, high-frequency interactions were identified for the vast majority of amino acid side chains ('structural code'). DNA binding specificities were then independently assessed by meta-analysis of random-mutagenesis studies of Zn finger-target DNA sequences. Selective, high-frequency interactions were identified for the majority of mutagenized residues ('mutagenesis code'). The structural code and the mutagenesis code were shown to match to a striking level of accuracy ( = 3.1 × 10), suggesting the identification of fundamental rules of TF binding to DNA bases. Additional insight was gained by showing a geometry-dictated choice among DNA-binding TF residues with overlapping specificity. These findings indicate the existence of a DNA recognition mode whereby the physical-chemical characteristics of the interacting residues play a deterministic role. The discovery of this DNA recognition code advances our knowledge on fundamental features of regulation of gene expression and is expected to pave the way for integration with higher-order complexity approaches.
转录因子（TF）氨基酸与DNA碱基之间的识别密码仍未得到充分理解。在此，通过对TF-DNA复合物晶体的分析，确定了TF氨基酸-DNA碱基结合选择性的决定因素。对于绝大多数氨基酸侧链（“结构密码”），识别出了选择性的高频相互作用。然后，通过对锌指靶向DNA序列的随机诱变研究进行荟萃分析，独立评估了DNA结合特异性。对于大多数诱变残基（“诱变密码”），识别出了选择性的高频相互作用。结果表明，结构密码和诱变密码在惊人的准确度水平上相匹配（ = 3.1 × 10），这表明确定了TF与DNA碱基结合的基本规则。通过展示在具有重叠特异性的DNA结合TF残基之间由几何结构决定的选择，获得了更多见解。这些发现表明存在一种DNA识别模式，其中相互作用残基的物理化学特征起着决定性作用。这种DNA识别密码的发现推进了我们对基因表达调控基本特征的认识，并有望为与更高阶复杂性方法的整合铺平道路。
