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

The FEBS journal Pub Date : 2024-11-01 Epub Date: 2024-09-29 DOI:10.1111/febs.17286
Yang Yang, Shuting Zhang, Li Xu, Yan Pan, Yumi Xuan, Yuanzhong Kai, Xuemin Chen
{"title":"Structural insights into the recognition of purine-pyrimidine dinucleotide repeats by zinc finger protein ZBTB43.","authors":"Yang Yang, Shuting Zhang, Li Xu, Yan Pan, Yumi Xuan, Yuanzhong Kai, Xuemin Chen","doi":"10.1111/febs.17286","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The FEBS journal","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1111/febs.17286","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/29 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

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.

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。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信