Modulating dynamics and function of nuclear actin with synthetic bicyclic peptides

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.

SUMOylation of Nuclear γ-Actin by SUMO2 supports DNA Damage Repair against Myocardial Ischemia-Reperfusion Injury

“…γ-Actin is encoded by the ACTG1 gene, widely expressed in many tissues and well recognized as a key component of the cellular cytoskeletons for regulating a wide range of cellular activities including cell motility, cell shape maintenance, polarity, chemotaxis, endocytosis and phagocytosis [45,46]. Increasing evidence indicates that γ-actin plays ermerging roles in the cell nuclear processes including chromatin remodeling, transcription, replication and DNA repair, representing a new frontier in cell biology [47][48][49]. The newly synthesized monomeric γ-actin is transported into the cell nucleus via importin-9 and regulated to form the dynamic equilibrium between monomeric globular form (G-form) and polymerised filamentous form (F-form) [50].…”

Current development of bicyclic peptides

“…11. Structure of bicyclic peptide BCP20.In 2020, Harata et al used a G-actin-binding bicyclic peptide to analyze and manipulate nuclear actin in cells[93].Because actin is involved in a wide range of cellular functions[94][95][96], the tools required for studying actin have become extremely desirable. There are many molecular tools obtained through extraction from natural sources or complex chemical synthesis procedures, but their inaccessibility makes their application less than ideal.…”