Structural insights into the recognition of purine-pyrimidine dinucleotide repeats by zinc finger protein ZBTB43

Yang Yang, Shuting Zhang, Li Xu, Yan Pan, Yumi Xuan, Yuanzhong Kai, Xuemin Chen
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Abstract

Purine-pyrimidine repeats (PPRs) can form left-handed Z-form DNA and induce DNA double-strand breaks (DSBs), posing a risk for genomic rearrangements and cancer. The zinc finger (ZF) and BTB domain-containing protein 43 (ZBTB43) is a transcription factor containing two Cys2-His2 (C2H2) and one C3H1 zinc fingers and plays a crucial role in maintaining genomic and epigenomic integrity by converting mutagenic Z-form PPRs to the B-form in prospermatogonia. Despite its importance, the molecular mechanism underlying the recognition of PPRs by ZBTB43 remains elusive. In this study, we determined the X-ray crystal structure of the ZBTB43 ZF1-3 in complex with the B-form DNA containing the CA repeats sequence. The structure reveals that ZF1 and ZF2 primarily recognize the CACA sequence through specific hydrogen-bonding and van der Waals contacts via a quadruple center involving Arg389, Met411, His413, and His414. These interactions were further validated by fluorescence-based DNA-binding assays using mutated ZBTB43 variants. Our structural investigation provides valuable insights into the recognition mechanism of PPRs by ZBTB43 and suggests a potential role for ZBTB43 in the transformation of Z-DNA to B-DNA, contributing to the maintenance of genomic stability.

Abstract Image

锌指蛋白 ZBTB43 识别嘌呤-嘧啶二核苷酸重复序列的结构研究。
嘌呤嘧啶重复序列(PPRs)可形成左手Z形DNA并诱导DNA双链断裂(DSBs),从而带来基因组重排和癌症风险。锌指(ZF)和含 BTB 结构域蛋白 43(ZBTB43)是一种转录因子,含有两个 Cys2-His2(C2H2)和一个 C3H1 锌指,通过在原精原细胞中将突变的 Z 型 PPR 转换为 B 型,在维持基因组和表观基因组完整性方面发挥着至关重要的作用。尽管 ZBTB43 非常重要,但其识别 PPRs 的分子机制仍然难以捉摸。在这项研究中,我们测定了 ZBTB43 ZF1-3 与含有 CA 重复序列的 B 型 DNA 复合物的 X 射线晶体结构。该结构显示,ZF1 和 ZF2 主要是通过涉及 Arg389、Met411、His413 和 His414 的四元中心,通过特定的氢键和范德华接触来识别 CACA 序列。使用突变的 ZBTB43 变体进行的基于荧光的 DNA 结合试验进一步验证了这些相互作用。我们的结构研究为 ZBTB43 识别 PPRs 的机制提供了宝贵的见解,并表明 ZBTB43 在 Z-DNA 转化为 B-DNA 的过程中可能发挥作用,有助于维持基因组的稳定性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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