Gene transcription and ubiquitin-mediated proteolysis are two processes that have seemingly nothing in common: transcription is the first step in the life of any protein and proteolysis the last. Despite the disparate nature of these processes, a growing body of evidence indicates that ubiquitin and the proteasome are intimately involved in gene control. Here, we discuss the deep mechanistic connections between transcription and the ubiquitin-proteasome system, and highlight how the intersection of these processes tightly controls expression of the genetic information.

Many transcription factors, particularly those involved in the control of cell growth, are unstable proteins destroyed by ubiquitin-mediated proteolysis. In a previous study of sequences targeting the transcription factor Myc for destruction, we observed that the region in Myc signaling ubiquitin-mediated proteolysis overlaps closely with the region in Myc that activates transcription. Here, we present evidence that the overlap of these two activities is not unique to Myc, but reflects a more general phenomenon. We show that a similar overlap of activation domains and destruction elements occurs in other unstable transcription factors and report a close correlation between the ability of an acidic activation domain to activate transcription and to signal proteolysis. We also show that destruction elements from yeast cyclins, when tethered to a DNA-binding domain, activate transcription. The intimate overlap of activation domains and destruction elements reveals an unexpected convergence of two very different processes and suggests that transcription factors may be destroyed because of their ability to activate transcription.

We report here that the prototypical yeast transcription factor Gal4 undergoes two distinct modes of ubiquitin-mediated proteolysis: one that occurs independent of transcription and restricts Gal4 function, and another that is transcription coupled and essential for productive activation of Gal4 target genes. Destruction of transcriptionally active Gal4 depends on an F box protein called Dsg1/Mdm30. In the absence of Dsg1, Gal4 is stable, nonubiquitylated, and unable to productively stimulate transcription. Analysis of the phenotype of dsg1-null yeast reveals a striking disconnect between GAL gene RNA and protein levels; in the absence of Dsg1, Gal4 target genes are transcribed, but the resulting RNAs are not translated. The translational defects of these RNAs are related to defects in phosphorylation of the RNA polymerase II carboxy-terminal domain, which in turn affects recruitment of RNA processing machinery. We propose that Gal4 ubiquitylation and destruction are required for initiation-competent transcription complexes to transition to fully mature elongating complexes capable of appropriate mRNA processing.

Promyelocytic leukaemia (PML) nuclear bodies are present in most mammalian cell nuclei. PML bodies are disrupted by PML retinoic acid receptor alpha (RAR alpha) oncoproteins in acute promyelocytic leukaemia. These bodies contain numerous proteins, including Sp100, SUMO-1, HAUSP(USP7), CBP and BLM, and they have been implicated in aspects of transcriptional regulation or as nuclear storage depots. Here, we show that three classes of PML nuclear bodies can be distinguished, on the basis of their dynamic properties in living cells. One class of PML bodies is particularly noteworthy in that it moves by a metabolic-energy-dependent mechanism. This represents the first example of metabolic-energy-dependent transport of a nuclear body within the mammalian cell nucleus.

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Research on astronaut health and model organisms have revealed six features of spaceflight biology that guide our current understanding of fundamental molecular changes that occur during space travel. The features include oxidative stress, DNA damage, mitochondrial dysregulation, epigenetic changes (including gene regulation), telomere length alterations, and microbiome shifts. Here we review the known hazards of human spaceflight, how spaceflight affects living systems through these six fundamental features, and the associated health risks of space exploration. We also discuss the essential issues related to the health and safety of astronauts involved in future missions, especially planned long-duration and Martian missions.

The limited number of in vivo germ cells poses an impediment to genome-wide studies. Here, we applied a small-scale chromatin immunoprecipitation sequencing (ChIP-seq) method on purified mouse fetal germ cells to generate genome-wide maps of four histone modifications (H3K4me3, H3K27me3, H3K27ac, and H2BK20ac). Comparison of active chromatin state between somatic, embryonic stem, and germ cells revealed promoters and enhancers needed for stem cell maintenance and germ cell development. We found the nuclear receptor Nr5a2 motif to be enriched at a subset of germ cell cis-regulatory regions, and our results implicate Nr5a2 in germ cell biology. Interestingly, in germ cells, the H3K27me3 histone modification occurs more frequently at regions that are enriched for retrotransposons and MHC genes, indicating that these loci are specifically silenced in germ cells. Together, our study provides genome-wide histone modification maps of in vivo germ cells and reveals the molecular chromatin signatures of germ cells.

Somatic G17V RHOA mutations were found in 50–70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1–STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1–STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1–STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA–VAV1 axis may provide a new therapeutic target in AITL.