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RNF4 is a prototypical single-subunit E3 enzyme that can bind both substrate and ubiquitin-loaded E2. Here, the authors show that the RNF4 N-terminal region, although lacking a defined secondary structure, maintains a compact global conformation to facilitate ubiquitin transfer to the substrate.

Taurine and indicine cattle have different desirable traits making them better adapted to different climates across the world. Here, Low et al. describe a pipeline to produce haplotype-resolved, chromosome-level genomes of Angus and Brahman cattle breeds from a crossbred individual and report on comparisons of the two genomes.

Structural and functional studies of Zinc finger antiviral protein and its cofactors, TRIM25 and KHYNYN, reveal the formation of complexes and suggest that multivalent recognition of CpG-rich RNA targets it for nucleolytic depletion.

The discovery that the anticancer activity of thalidomide and its analogues, such as lenalidomide, reflects drug-induced degradation of specific target proteins has heightened interest in novel ‘degrader’ drugs. Herein, the authors review the wide and expanding use of thalidomide analogues in the treatment of multiple cancers and outline how lessons learned from this experience, particularly with lenalidomide, can guide the clinical development of new targeted protein degradation platforms.

Hyer et al. generate a potent and specific small-molecule inhibitor of the E1 ubiquitin-activating enzyme UBE1 that has antitumor activity in mice against a wide variety of tumor types.

A potent and selective degrader was developed that depletes STAT5 in cells and mouse tissues, exerts cell growth inhibition in cells with activated STAT5 and induces tumor regression in mouse models.

Advanced E2-modified ubiquitin probes enable investigation of E2-selective ubiquitination in cells and the discovery of tyrosine ubiquitination as a modification occurring in a UBE2D3-specific manner.

The protein Cereblon, part of an ubiquitin E3 ligase complex, is the target for anticancer thalidomide analogs. The crystal structure of human Cereblon-DDB1 with bound lenalidomide reveals how the drug affects E3 substrate recruitment.

In fission yeast, the septum initiation network (SIN) regulates septation at the end of mitosis. Hagan and colleagues now reveal a further role for the SIN kinase Sid2 that is independent of other known SIN components, in the control of entry into mitosis through phosphorylation of the NIMA kinase Fin1.

TRIM21 mediates intracellular antibody immunity and is exploited for targeted protein degradation using Trim-Away technology. Here, the authors dissect the ubiquitination requirements for Trim-Away, providing an explanation for how TRIM21 can target diverse substrates for degradation.

Iron homoeostasis is tightly orchestrated to avoid toxic iron overload. Here Lim and colleagues show that iron excess activates Nrf2 via mitochondrial reactive oxygen species, enhancing the expression of Bmp6 in liver sinusoidal endothelial cells, which in turn promotes hepcidin expression by hepatocytes, decreasing systemic iron levels.

The cyclin-dependent kinase (Cdk) inhibitor p27 regulates cell proliferation, cell motility and apoptosis, and is inactivated through various means in many types of human cancer. Recent studies in several tumour types indicate that p27 expression levels have both prognostic and therapeutic implications.

We show that gain-of-function cancer mutations in the KBTBD4 E3 ligase promote neodegradation of substrates via a shape-complementarity-based mechanism, which converges with the mechanism of action of the UM171 molecular glue degrader and can be blocked by HDAC1/2 inhibitors.

Lenalidomide, a derivative of thalidomide, is an effective drug for myelodysplastic syndrome; lenalidomide binds the CRL4^CRBN E3 ubiquitin ligase and promotes degradation of casein kinase 1a, on which the malignant cells rely for survival.

The dTAG system pairs potent heterobifunctional degraders and extensible tagging strategies to achieve immediate and reversible degradation of divergent proteins, facilitating biological investigation and drug target validation in cells and in mice.

The transcription factor REST plays important roles in opposing neuronal differentiation and in some human tumours. β-TrCP is identified as an important regulator of REST degradation.

Redox signalling in the gastrointestinal mucosa is held in an intricate balance. This Review addresses both the spectrum and intensity of redox activity pertaining to host–immune and host–microbiota crosstalk during homeostasis and disease processes in the gastrointestinal tract.

SOCS3 is an important negative feedback inhibitor of JAK–STAT-mediated cytokine signalling. Here the authors implicate cavin-1 — an essential component of caveolae — in the recruitment of SOCS3 to the plasma membrane to prevent sustained cytokine receptor signalling.

The telomerase holoenzyme is minimally composed of the reverse transcriptase and the RNA template. Here the authors identify Lar7 as a member of the full complex that helps to stabilise it and protect telomerase RNA from degradation.

Characterization of DCAF16-based BRD4 molecular glue degraders revealed a trans-labeling mechanism termed ‘template-assisted covalent modification’, which opens a new path for proximity-driven pharmacology.

PROTACs enable targeted protein degradation by recruiting an E3 ligase to a specific substrate but the determinants of selectivity are not fully understood. Here, the authors show that varying the linker between warhead and E3 ligand and the orientation of the E3 ligase allow tuning PROTAC selectivity toward different p38 isoforms.

A systems approach provides a global perspective of the different strategies that viruses use to modulate the cellular innate immune response; this may be useful in the design of future viral intervention strategies.

Whole-genome sequencing of 78 Icelandic parent–offspring trios is used to study the de novo mutation rate at the genome-wide level; the rate is shown to increase by about two mutations a year as a function of the increasing age of the father at conception, highlighting the importance of father’s age on the risk of diseases such as autism and schizophrenia.

Huang and colleagues uncover a key role of phosphorylation in enhancing the activity of Arabidopsis master growth regulator DELLA by promoting its interaction with histone H2A at target chromatin.

Here, Richard Kolodner and colleagues use assays in Saccharomyces cerevisiaeto identify 182 genetic modifiers of gross chromosomal rearrangements (GCRs). They also compared these Genome Instability Suppressing (GIS) genes and pathways in human cancer genome, and found many ovarian and colorectal cancer cases have alterations to GIS pathways.

Several ubiquitin ligases are altered in cancer. These proteins are crucial for the ubiquitin-mediated degradation of cell-cycle proteins, ensuring regulated progression through the cycle. Understanding the mechanistic roles of these ligases is therefore of great importance.

Inflammasome assembly promotes the cleavage and oligomerisation of gasdermin D (GSDMD) and subsequent pore formation. Here the authors raise nanobodies to human gasdermin and characterize the pore formation process mediated by GSDMD and how antagonistic nanobodies prevent pyroptosis.

Vpr is a HIV-1 accessory virulence factor that also interacts with the human DNA repair protein hHR23A. Here, the authors present the structure of Vpr in complex with the C-terminal half of hHR23A comprising the XPC-binding and ubiquitin-associated domains, which reveals that hHR23A interacts with the DCAF1-binding and not the substrate-binding Vpr surface and further illustrates how Vpr acts as a versatile structural adapter that targets diverse DNA repair pathways.

Aifantis and colleagues report that FBXW7α controls the heat-shock response pathway by targeting HSF1 for degradation. In melanoma FBXW7α deficiency leads to increased nuclear HSF1, and induction of a pro-invasive gene expression program.

The parasite Cryptosporidium has a reduced genome and is dependent on glycolysis for energy production. Here, Xu et al demonstrate that multiple pathways and glucose transporters exist in this organism which are essential for growth and facilitate energy acquisition and utilization.

An epistatic miniarray profile allows identification of multiprotein complexes involved in various aspects of chromosome biology. In one pathway, the histone acetyltransferase Rtt109 is found to modify histone H3 lysine 56 during DNA replication.

A high-throughput DNA-encoded library (DEL)-based screening approach was developed for the discovery of proximity-inducing small molecules.

Salicylic acid (SA) signaling pathway restricts the compatible infection of potyviruses. Here, Liu et al. show that potyviral NIb interacts with NPR1, the SA receptor in plants, preventing its sumoylation by SUMO3 and subsequent phosphorylation at Ser11/Ser15. This way, NPR1-mediated immunity is suppressed to promote virus infection.

Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.

The authors find that deletion from Schwann cells of an E3 ubiquitin ligase component called Fbxw7 leads to a phenotype reminiscent of myelination in the central nervous system where a single oligodendrocyte ensheaths multiple axons.

Cryo-EM and three-dimensional variability analyses reveal the structure of the autoinhibited 640-kDa NF1 dimer, providing a long-sought-after molecular explanation for the extreme sensitivity of the NF1 gene to loss-of function mutation in disease.

Immune cells produce reactive oxygen species (ROS) to eliminate pathogens, but cell-spontaneous death and ageing may also be induced. Here the authors show that, upon sensing ROS, Mst1/2 kinases modulate the activity of Nrf2 transcription factor and downstream genetic programs to protect mouse macrophages from death and ageing.

Combination of drugs within cancer treatment is a popular way to overcome resistance and increase efficacy. Here, the authors analyse over 5000 targeted agent combinations in non-small cell lung cancer to identify potentially effective drug strategies.

Ancestral land plants had a free-living gametophyte, but in flowering plants the gametophyte develops within the sporophyte. This study shows that male gametophyte development in Arabidopsis is directed by the sporophyte through repression of gametogenesis genes.

Analysis of whole-genome doubling (WGD) by using cancer sequencing data combined with simulations of tumor evolution suggests that there is negative selection against homozygous loss of essential genes before WGD but not after.

A short isoform of the Tet1 enzyme (Tet1s) that oxidizes the DNA 5-methylcytosine (5mC) mark is overexpressed in tumors. Here the authors show Tet1s, but not full length Tet1, changes localization over the cell cycle upon ubiquitination and Uhrf1 interaction and is targeted to heterochromatin during S-phase. This leads to 5mC oxidation and loss of DNA methylation in heterochromatin.

Nucleotide excision repair proteins are involved in the repair of UV-induced DNA damage. Here, the authors show that NER proteins, DDB2, XPC, and XPA play a vital role in the 8-oxoguanine repair by coordinating with base excision repair protein OGG1.