Modulating dynamics and function of nuclear actin with synthetic bicyclic peptides. (10th November 2020)

• Record Type: Journal Article
• Authors: Machida, Nanako; Takahashi, Daisuke; Ueno, Yuya; Nakama, Yoshihiro; Gubeli, Raphael J; Bertoldo, Davide; Harata, Masahiko
• Is Part Of: Journal of biochemistry. Volume 169:Number 3(2021)
• Page Start: 295
• Page End: 302
• Publication Date: 2020-11-10
• Subjects: actin-binding molecule -- actin polymerization -- bicyclic peptide -- gene expression -- nuclear actin; Biochemistry -- Periodicals; Biochemistry -- Periodicals; Electronic journals; 572.05
• DOI: 10.1093/jb/mvaa130
• Languages: English
• ISSNs: 0021-924X

Abstract

Abstract: Actin exists in monomeric globular (G-) and polymerized filamentous (F-) forms and the dynamics of its polymerization/depolymerization are tightly regulated in both the cytoplasm and the nucleus. Various essential functions of nuclear actin have been identified including regulation of gene expression and involvement in the repair of DNA double-strand breaks (DSB). Small G-actin-binding molecules affect F-actin formation and can be utilized for analysis and manipulation of actin in living cells. However, these G-actin-binding molecules are obtained by extraction from natural sources or through complex chemical synthesis procedures, and therefore, the generation of their derivatives for analytical tools is underdeveloped. In addition, their effects on nuclear actin cannot be separately evaluated from those on cytoplasmic actin. Previously, we have generated synthetic bicyclic peptides, consisting of two macrocyclic rings, which bind to G-actin but not to F-actin. Here, we describe the introduction of these bicyclic peptides into living cells. Furthermore, by conjugation to a nuclear localization signal (NLS), the bicyclic peptides accumulated in the nucleus. The NLS-bicyclic peptides repress the formation of nuclear F-actin, and impair transcriptional regulation and DSB repair. These observations highlight a potential role for NLS-linked bicyclic peptides in the manipulation of dynamics and functions of nuclear actin. Graphical Abstract: