Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China.
MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, 30 Shuangqing Road, Beijing 100084, China.
Nucleic Acids Res. 2024 Oct 14;52(18):11349-11361. doi: 10.1093/nar/gkae762.
The BEN domain is a newly discovered type of DNA-binding domain that exists in a variety of species. There are nine BEN domain-containing proteins in humans, and most have been shown to have chromatin-related functions. NACC1 preferentially binds to CATG motif-containing sequences and functions primarily as a transcriptional coregulator. BANP and BEND3 preferentially bind DNA bearing unmethylated CpG motifs, and they function as CpG island-binding proteins. To date, the DNA recognition mechanism of quite a few of these proteins remains to be determined. In this study, we solved the crystal structures of the BEN domains of NACC1 and BANP in complex with their cognate DNA substrates. We revealed the details of DNA binding by these BEN domain proteins and unexpectedly revealed that oligomerization is required for BANP to select unmethylated CGCG motif-containing DNA substrates. Our study clarifies the controversies surrounding DNA recognition by BANP and demonstrates a new mechanism by which BANP selects unmethylated CpG motifs and functions as a CpG island-binding protein. This understanding will facilitate further exploration of the physiological functions of the BEN domain proteins in the future.
BEN 结构域是一种新发现的 DNA 结合结构域，存在于多种物种中。人类中有 9 种含有 BEN 结构域的蛋白质，大多数已被证明具有与染色质相关的功能。NACC1 优先结合含有 CATG 基序的序列，并主要作为转录共调节剂发挥作用。BANP 和 BEND3 优先结合带有未甲基化 CpG 基序的 DNA，它们作为 CpG 岛结合蛋白发挥作用。迄今为止，这些蛋白质中的相当一部分的 DNA 识别机制仍有待确定。在这项研究中，我们解决了 NACC1 和 BANP 的 BEN 结构域与它们的同源 DNA 底物复合物的晶体结构。我们揭示了这些 BEN 结构域蛋白结合 DNA 的细节，并出人意料地揭示了寡聚化是 BANP 选择未甲基化 CGCG 基序含有 DNA 底物所必需的。我们的研究澄清了围绕 BANP 的 DNA 识别的争议，并展示了 BANP 选择未甲基化 CpG 基序并作为 CpG 岛结合蛋白发挥作用的新机制。这一理解将有助于未来进一步探索 BEN 结构域蛋白的生理功能。
