Recent advances in nuclear actin research

Abstract

Actin was first observed in the nucleus more than sixty years ago but research on nuclear actin did not receive significant attention for the next forty years. It only started to accelerate around the year 2000, when the first convincing experimental data emerged indicating that actin participates in essential nuclear processes. Today, we know that actin is involved in transcription, replication, DNA repair, chromatin remodeling, and participates in the determination of nuclear shape and size. In this paper we review the results of the last five years of increasingly intensive research on nuclear actin, because on one hand, the field has expanded with several new directions during this time, and on the other hand, the enrichment of our picture of nuclear actin will certainly provide a more solid foundation and new impetus for its future investigation.

Keywords: Actin; DNA repair; chromatin; development; disease; nuclear transport; nucleus; phase separation; replication; transcription.

Figure 1.

A comprehensive summary of the newly discovered, diverse functions of nuclear actin. (a) Nuclear actin polymerization has been shown to be crucial for Pol2 clustering in response to different stimuli. Pol2 - RNA polymerase 2, AR – Androgen receptor, DHT – Dihydro-testosterone, INF2 - Inverted formin 2, SUN2 - SUN domain-containing protein 2, MED15 - Mediator of RNA polymerase II transcription subunit 15, Hsf – Heat shock factor protein, dMoe – Drosophila Moesin, DAAM2 - Disheveled-associated activator of morphogenesis 2, ARP2/3 - Actin-related protein 2/3 complex, nWasp - Neural Wiskott-Aldrich syndrome protein, MYO6 – Myosin VI. (b) Local actin polymerization acts as a framework for replication fork stalling and repair in the event of replication stress. ATR – ataxia telangiectasia and Rad3-related protein, PCNA – Proliferating cell nuclear antigen, NMII – Non-muscle myosin II, PrimPol – DNA-directed primase/polymerase protein, DIAPH1 - Diaphanous related formin 1, RPA – Replication protein A. (c) Nuclear actin fibers are required for chromatin and PML body movement, repair factor clustering and limiting access of other factors upon DNA damage. dsbNET – DSB-capturing nuclear envelope tubules, RPA – Replication protein A, TERT – Telomerase reverse transcriptase, PML – Promyelocytic leukemia nuclear body, p53 - Cellular tumor antigen p53, DYRK1A – Dual specificity tyrosine-phosphorylation-regulated kinase 1A, RHOJ – Rho-related GTP-binding protein, NM1 - Nuclear Myosin 1, p21 - Cyclin-dependent kinase inhibitor 1. (d) Monomeric actin acts as a component of chromatin remodeling complexes, while filamentous actin provides a scaffold for chromatin movement. KAT14 - Cysteine-rich protein 2-binding protein, INO80 - Chromatin-remodeling ATPase INO80, BAF – BRG1/BRM-associated factor complex, BRG1 - Brahma homolog 1, EZH2 - Enhancer of Zeste homolog 2, green DNA segment – Hsp70 locus. (e) Several actin-binding proteins (ABP) contain disordered protein regions, possibly contributing to phase separation involving actin, not only in the cytoplasm, but also in the nucleus. LLPS – liquid-liquid phase separation.(f) the nuclear transport of actin is assured by multiple factors. Cdm – Cadmus, Msk – Moleskin, PFN – Profilin, CFL – Cofilin, IPO9 – Importin 9, ß-CAT - ß-Catenin, XPO6 – Exportin 6. (g) Through its role in transcription and chromatin remodeling, actin is part of several developmental pathways. MKL1 - Myocardin-like protein 1/MRTF-A, SRF – Serum response factor, YAP/TAZ – Yes-associated protein/WW domain-containing transcription regulator protein 1, TEAD – TEA domain transcription factor, MYPOP – Myb-related transcription factor, partner of profilin, MYBBP1A – Myb-binding protein 1A, NKRF – NF-kappa-B-repressing factor, EMT – epithelial-mesenchymal transition. (h) Both the monomer and polymer forms of actin are factors in pathogenic processes, such as migration of cancer cells and response to injury. mDia2 - Diaphanous-related formin protein 2, TFAM – Mitocondrial transcription factor A, RASSF1A – Ras association domain-containing protein 1, MRTF-A - Myocardin-related transcription factor A. The actin filament is symbolized by a double helix made up of round, dark red G-actin monomers, and DNA is symbolized by a blue wavy line. See text for further details.