Abstract:SummaryActin has been linked to processes spanning the whole gene expression cascade, from regulating specific transcription factors, such as myocardin-related transcription factor, to chromatin remodeling and RNA polymerase function. However, whether actin controls the transcription of only specific genes or has a global role in gene expression has remained elusive. Our genome-wide analysis reveals, for the first time, that actin interacts with essentially all transcribed genes in Drosophila ovaries. Actin co… Show more
“…These findings imply that actin could be directly associated with pre-mRNA splicing/processing complexes. Alternatively, the co-transcriptional nature of splicing (Herzel et al, 2017), and the involvement of actin in transcription (Fomproix and Percipalle, 2004; Hofmann et al, 2004; Kukalev et al, 2005; Obrdlik et al, 2008; Percipalle et al, 2003; Philimonenko et al, 2004; Sokolova et al, 2018), may explain the detection of the RNA splicing/processing-related proteins. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Actin has also been linked directly to the transcription process, because it can be co-purified with all three RNA polymerase (Pol) complexes: Pol I (Fomproix and Percipalle, 2004), Pol II (Egly et al, 1984; Smith et al, 1979) and Pol III (Hu et al, 2004). The precise molecular mechanisms by which actin participates in transcription are still unclear, but balanced nucleo-cytoplasmic shuttling of actin is necessary for transcription (Dopie et al, 2012; Sokolova et al, 2018). Availability of nuclear actin monomers seems to be critical here, since polymerization of nuclear actin into stable filaments (Serebryannyy et al, 2016b) or activation of a mechanosensory complex consisting of emerin, non-muscle myosin II and actin (Le et al, 2016) repress transcription.…”
Section: Introductionmentioning
confidence: 99%
“…Our recent genome-wide analysis revealed that actin interacts with essentially all transcribed genes. Actin is found, together with Pol II, near the transcription start sites of most genes, as well as on the gene bodies of highly expressed genes (Sokolova et al, 2018). Actin may thus have several functions during the transcription process, and has, in fact, been implicated in pre-initiation complex (PIC) assembly (Hofmann et al, 2004) as well as transcription elongation via the pTEF-β complex (Qi et al, 2011).…”
In addition to its essential functions within the cytoskeleton, actin also localizes to the cell nucleus, where it is linked to many important nuclear processes from gene expression to maintenance of genomic integrity. However, the molecular mechanisms by which actin operates in the nucleus remain poorly understood. Here, we have used two complementary mass spectrometry (MS) techniques, AP-MS and BioID, to identify binding partners for nuclear actin. Common high-confidence interactions highlight the role of actin in chromatin-remodeling complexes and identify the histone-modifying complex human Ada-Two-A-containing (hATAC) as a novel actin-containing nuclear complex. Actin binds directly to the hATAC subunit KAT14, and modulates its histone acetyl transferase activity
in vitro
and in cells. Transient interactions detected through BioID link actin to several steps of transcription as well as to RNA processing. Alterations in nuclear actin levels disturb alternative splicing in minigene assays, likely by affecting the transcription elongation rate. This interactome analysis thus identifies both novel direct binding partners and functional roles for nuclear actin, as well as forms a platform for further mechanistic studies on how actin operates during essential nuclear processes.
.
“…These findings imply that actin could be directly associated with pre-mRNA splicing/processing complexes. Alternatively, the co-transcriptional nature of splicing (Herzel et al, 2017), and the involvement of actin in transcription (Fomproix and Percipalle, 2004; Hofmann et al, 2004; Kukalev et al, 2005; Obrdlik et al, 2008; Percipalle et al, 2003; Philimonenko et al, 2004; Sokolova et al, 2018), may explain the detection of the RNA splicing/processing-related proteins. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Actin has also been linked directly to the transcription process, because it can be co-purified with all three RNA polymerase (Pol) complexes: Pol I (Fomproix and Percipalle, 2004), Pol II (Egly et al, 1984; Smith et al, 1979) and Pol III (Hu et al, 2004). The precise molecular mechanisms by which actin participates in transcription are still unclear, but balanced nucleo-cytoplasmic shuttling of actin is necessary for transcription (Dopie et al, 2012; Sokolova et al, 2018). Availability of nuclear actin monomers seems to be critical here, since polymerization of nuclear actin into stable filaments (Serebryannyy et al, 2016b) or activation of a mechanosensory complex consisting of emerin, non-muscle myosin II and actin (Le et al, 2016) repress transcription.…”
Section: Introductionmentioning
confidence: 99%
“…Our recent genome-wide analysis revealed that actin interacts with essentially all transcribed genes. Actin is found, together with Pol II, near the transcription start sites of most genes, as well as on the gene bodies of highly expressed genes (Sokolova et al, 2018). Actin may thus have several functions during the transcription process, and has, in fact, been implicated in pre-initiation complex (PIC) assembly (Hofmann et al, 2004) as well as transcription elongation via the pTEF-β complex (Qi et al, 2011).…”
In addition to its essential functions within the cytoskeleton, actin also localizes to the cell nucleus, where it is linked to many important nuclear processes from gene expression to maintenance of genomic integrity. However, the molecular mechanisms by which actin operates in the nucleus remain poorly understood. Here, we have used two complementary mass spectrometry (MS) techniques, AP-MS and BioID, to identify binding partners for nuclear actin. Common high-confidence interactions highlight the role of actin in chromatin-remodeling complexes and identify the histone-modifying complex human Ada-Two-A-containing (hATAC) as a novel actin-containing nuclear complex. Actin binds directly to the hATAC subunit KAT14, and modulates its histone acetyl transferase activity
in vitro
and in cells. Transient interactions detected through BioID link actin to several steps of transcription as well as to RNA processing. Alterations in nuclear actin levels disturb alternative splicing in minigene assays, likely by affecting the transcription elongation rate. This interactome analysis thus identifies both novel direct binding partners and functional roles for nuclear actin, as well as forms a platform for further mechanistic studies on how actin operates during essential nuclear processes.
.
“…ytoskeletal proteins such as actin and myosin have emerged as key factors in the regulation of a dynamic chromatin landscape compatible with active transcription 1 . Actin and a specific isoform of myosin 1c referred to as nuclear myosin 1 (NM1) associate with the genome in both insects and mammals [2][3][4] . Actin and NM1 synergize with all three nuclear RNA polymerases and chromatin remodelers to initiate and activate transcription 5,6 .…”
Nuclear myosin 1 (NM1) has been implicated in key nuclear functions. Together with actin, it has been shown to initiate and regulate transcription, it is part of the chromatin remodeling complex B-WICH, and is responsible for rearrangements of chromosomal territories in response to external stimuli. Here we show that deletion of NM1 in mouse embryonic fibroblasts leads to chromatin and transcription dysregulation affecting the expression of DNA damage and cell cycle genes. NM1 KO cells exhibit increased DNA damage and changes in cell cycle progression, proliferation, and apoptosis, compatible with a phenotype resulting from impaired p53 signaling. We show that upon DNA damage, NM1 forms a complex with p53 and activates the expression of checkpoint regulator p21 (Cdkn1A) by PCAF and Set1 recruitment to its promoter for histone H3 acetylation and methylation. We propose a role for NM1 in the transcriptional response to DNA damage response and maintenance of genome stability.
“…Actin polymerization is required for this interaction, suggesting an independent and direct role for F-actin in MRTF-A activation 23 . Actin, actin polymerizing proteins, and myosins also associate with RNA polymerases and transcription sites [24][25][26][27][28] , and actin dynamics are required for polymerase activity 27,[29][30][31][32] . However, RNA polymerase-associated actin appears mostly monomeric 27 , and whether nuclear actin filaments are specifically and directly involved in these responses is still unclear.…”
Actin filaments (F-actin) have well-known functions in the cytoplasm, including generating forces for cell movement and enabling myosin-driven dynamics of vesicles and mRNAs. In addition, the recent development of innovative tools for F-actin detection have revealed dynamic and transient filaments in the nuclei, which form in response to specific stimuli. Here we provide an overview of the functions of F-actin and myosins in nuclei, with a focus on their role in DNA repair and genome stability. We emphasize recent discoveries of nuclear F-actin driving the relocalization of heterochromatic repair sites to the nuclear periphery for ‘safe' homologous recombination (HR) repair of double-strand breaks (DSBs). F-actin also promotes repair focus clustering and DSB resection in euchromatin, facilitating HR progression. We highlight regulatory mechanisms specialized for actin polymerization during DNA replication and repair, and emphasize recent studies revealing alternative motors for the directional movement of repair sites. Together, these discoveries challenge previous models that actin is substantially monomeric in the nucleus and that DSBs move via Brownian motion, revealing a complex network of dynamic filaments, motors and regulators, coordinating chromatin dynamics with repair progression.
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