Nuclear myosin 1 activates p21 gene transcription in response to DNA damage through a chromatin-based mechanism

Abstract

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.

Limited Proteolysis-Coupled Mass Spectrometry Identifies Phosphatidylinositol 4,5-Bisphosphate Effectors in Human Nuclear Proteome

“…The importance of actin in the activity of Pol I and Pol II has also been documented [ 37 , 39 ]. Therefore, the presented PIPsLiP-qMS identification of the PIP2-effectors associated with actin cytoskeleton is in agreement with the previous studies that showed involvement of nucleoskeleton in the regulation of gene expression [ 37 , 38 , 39 , 40 , 41 ]. Moreover, the novel PIP2-binding actin- and cytoskeleton-related proteins identified here are interesting candidates for further studies.…”

Regulation of oxidative phosphorylation by Nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

“…RTqPCR analysis of nuclear-encoded OXPHOS genes, representing all five subunits of the OXPHOS chain (Ndufs1, SDHA, UQCRB, Cox5A, and ATPf51) and mitochondrial-encoded OXPHOS genes (mt-CO1, mt-Cyb, and mt-ND1) confirmed the results from immunoblots (Figure 1C and 1D) (Supplementary table 1). In addition, analysis of RNA sequencing data from primary mouse embryonic fibroblasts (Venit et al, 2020b) derived from NM1 WT and KO embryos (Venit et al, 2013) corroborated the above findings and further demonstrated that the majority of differentially expressed OXPHOS genes are downregulated in NM1 KO cells (Figure 1E) supporting previous results observed in stable NM1 KO MEFs. The comparison of all differentially expressed genes with all genes under the MGI Gene Ontology (GO) term "Mitochondrion" (GO:0005739) revealed a high correlation between the groups with over 40% of all mitochondria-associated genes being differentially expressed in the NM1 KO condition (Figure 1F) affecting processes such as mitochondrial organization, translation, and transport together with previously described OXPHOS (Figure 1G).…”

Nuclear myosin VI regulates the spatial organization of mammalian transcription initiation

“…It remains to be explored if both proteins interact with RNAPII simultaneously to stabilise the complex or if, conversely, the different myosin proteins interact with distinct populations of RNAPII. Overall, it would not be surprising if nuclear myosins are deployed in a similar way in other nuclear processes such as DNA repair, where myosin proteins are also known to function (Caridi et al, 2018, Kulashreshtha et al, 2016, Venit et al, 2020. Upon perturbation of myosin VI, RNAPII was observed around the nuclear periphery, which highlights the key role of myosin VI in maintaining the nuclear organisation of RNAPII.…”