5-Formyluracil targeted biochemical reactions with proteins inhibit DNA replication, induce mutations and interference gene expression in living cells

• Published in: Chinese chemical letters Vol. 32; no. 10; pp. 3252 - 3256
• Main Authors: Zou, Guangrong, Zhang, Kaiyuan, Yang, Wei, Liu, Chaoxing, Fang, Zhentian, Zhou, Xiang
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-10-2021; College of Chemistry and Molecular Sciences,Key Laboratory of Biomedical Polymers of Ministry of Education,The Institute for Advanced Studies,Hubei Province Key Laboratory of Allergy and Immunology Wuhan University,Wuhan 430072,China
• Subjects: 5-Formyluracil; Biochemical reaction; DNA replication; Gene expression; Mutation; 5-Formyluracil; DNA replication; Mutation; Biochemical reaction; Gene expression
• ISSN: 1001-8417; 1878-5964
• DOI: 10.1016/j.cclet.2021.02.036

By introducing 5-formyluracil (5fU) based covalent DNA-peptide or DNA-protein cross-links into DNA duplexes and using various methods, this study demonstrates the first attempt to explore the functional impacts of 5fU intermediated biochemical reactions between peptides or proteins on DNA replication, transcription and gene expression in vitro and in living cells.
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Covalent DNA–protein cross-links are toxic DNA lesions that interfere with essential biological processes, which can cause serious biological consequences, such as genomic instability and protein misexpression. 5-Formyluracil (5fU) as an important modification in DNA, which is mainly from oxidative damage, exists in a variety of cells and tissues. We have reported that 5fU mediated DNA–protein conjugates could exist in human cells [Zhou et al. CCS Chem. 2 (2020) 54–63]. We now aimed to explore its potential biological effects in vitro and in vivo. In this paper, we firstly reported that 5fU intermediated DNA–peptide or DNA–protein conjugates (both were called DPCs) could inhibit different polymerases bypass or cause mutations. Then we further investigated the functional impacts caused by 5fU-mediated DPCs, which appeared in different gene expression components [in the promoter sequence or 5′-untranslated regions (UTR)]. These results together may contribute to a broader understanding of DNA–protein interactions as well as the biological functions associated with 5fU.