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The E3 ubiquitin ligase TRAIP governs the choice between the NEIL3 or the Fanconi anaemia pathway for the repair of DNA interstrand crosslinks.

High methionine and S-adenosylmethionine serum levels are related with obesity. Here the authors show that knockdown of methionine adenosyltransferase by using antisense oligonucleotides provides beneficial effects in obesity and comorbidities.

NLRP6 is highly expressed in the gut; however, persistent NLRP6 activation can lead to excessive IL-18 production and intestinal bowel disease. Venuprasad and colleagues identify the K63-linked ubiquitin deubiquitinase Cyld as a negative regulator of NLRP6.

The SUMO-targeted ubiquitin ligase RNF111 promotes K63-linked ubiquitylation of SUMOylated XPC after DNA damage. Here the authors show that RNF111 is responsible for sequential XPC ubiquitylation, and RNF111-mediated ubiquitylation promotes the release of XPC from damaged DNA after NER initiation.

Malignant mixed Müllerian tumours are a rare and aggressive gynaecological cancer with poor 5-year survival rates. Here, the authors characterize the mutational landscape of carcinosarcomas and highlight the role of chromatin remodelling dysregulation in carcinosarcoma tumorigenesis.

This is one of two papers demonstrating that in several cancer types including ovarian cancer and T-cell leukaemias, the apoptosis regulator MCL1 is targeted for degradation by the FBW7 tumour suppressor. This study finds that this mechanism can determine the response to drugs targeting BCL2 family apoptosis factors. Deletion or mutation of FBW7 found in cancer patients therefore can render tumours resistant to these therapies.

Auxin-mediated recruitment of AUX/IAAs by the F-box protein TIR1 prompts rapid AUX/IAA ubiquitylation and degradation. By resolving auxin receptor topology, the authors show that intrinsically disordered regions near the degrons of two Aux/IAA proteins reinforce complex assembly and position Aux/IAAs for ubiquitylation.

Structural studies of the dimerization quality control E3 ubiquitin ligase SCF–FBXL17 indicate that its selectivity for aberrant complex formation is based on recognizing both shape and complementarity of interacting domains.

Directed protein degradation to target hard-to-drug proteins is a promising therapeutic approach. Here, the authors report the prospective discovery of small molecule “molecular glue” that inserts into a naturally occurring E3 ligase-substrate interface leading to degradation of substrate protein.

Whole genome sequencing and genome-wide association studies of ash trees affected by the invasive alien fungus Hymenoscyphus fraxineus are used to train a genomic prediction model, which could predict tree health with >65% accuracy.

Phytochrome photoreceptors mediate degradation of PIF transcription factors in the nucleus in response to light. Here Niet al. identify a family of nuclear protein kinases that interact with photoactivated phytochrome B and facilitate phytochrome-induced phosphorylation and degradation of PIF3.

DNA replication processes are often dysregulated in cancer. Here the authors analyse DNA synthesis patterns in cancer cells undergoing partial genome re-replication to reveal that re-replication exhibits aberrant replication fork dynamics and a skewed distribution of replication initiation that over-duplicates early-replicating genomic regions.

JASMONATE-INSENSITIVE 3 (JAI3) and a family of related proteins named JAZ (jasmonate-ZIM-domain) are identified. JAI3 and some of the other JAZ proteins interact with the SCF^COI1 ubiquitin ligase complex. Additionally JAI3 and JAZ1 interact with AtMyc2, a key transcriptional activator of jasmonate-regulated gene expression.

Genomic analysis of 491 medulloblastoma samples, including methylation profiling of 1,256 cases, effectively assigns candidate drivers to most tumours across all molecular subgroups.

Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.

Selective TRIM24 degradation is achieved by co-opting the VHL E3 ubiquitin ligase machinery. TRIM24 degradation outperforms bromodomain inhibition, with an enhanced antiproliferative effect in acute leukemia, a novel context of TRIM24 dependency.

The genetic factors involved in disease progression and drug resistance in multiple myeloma (MM) are varied and complex. Here, genomic and transcriptomic profiling of 511 relapsed and refractory MM patients reveals genetic alterations in several oncogenic pathways contributing to progression and resistance to MM therapies.

Most proteins are degraded and regulated by the 26S proteasome. A balance of specificity and promiscuity underlies substrate recognition and ATP-dependent degradation, which can occur in a ubiquitin-dependent or ubiquitin-independent manner. Recent insights into the mechanisms and regulation of substrate delivery, processing and degradation will inform new strategies for the treatment of human diseases.

Boztug and colleagues identify an immunodeficient patient with a deficiency in the guanine-nucleotide-exchange factor RASGRP1. They find that human RASGRP1 is important for the function of T cells, B cells and NK cells and that it has a role in the regulation of the cytoskeleton.

The plant auxin receptor TIR1 needs to associate with the SCF complex to be functional and target substrates. Newly discovered mutations that can block this interaction suggest that TIR1 is autocatalytically degraded once assembled in the SCF complex.

Quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of genomically annotated human breast cancer samples elucidates functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies potential therapeutic targets.

The crystal structures of thalidomide and its derivatives bound to the E3 ligase subcomplex DDB1–CRBN are shown; these drugs are found to have dual functions, interfering with the binding of certain cellular substrates to the E3 ligase but promoting the binding of others, thereby modulating the degradation of cellular proteins.

DNA double-strand break (DSB) repair is a tightly regulated process that can occur via non-homologous end joining (NHEJ) or homologous recombination (HR). Here, the authors investigate how RECQL4 modulates DSB repair pathway choice by differentially regulating NHEJ and HR in a cell cycle-dependent manner.

Sirtuins are involved in the regulation of responses to diverse types of cellular stress. Here the authors describe the SirT6-dependent cysteine monoubiquitination of the histone methyltransferase Suv39h1 as part of a regulatory circuit for the NF-κB pathway.

HIV-1 integration into host DNA is mediated by the viral integrase (IN). Here, using siRNA screen and high-content microscopy, the authors identify the host E3 RING ligase TRIM33 to affect IN stability and show that TRIM33 prevents viral integration by triggering IN proteasome-mediated degradation.

In recent years, nine new human polyomaviruses have been discovered, including Merkel cell polyomavirus, which has been linked to Merkel cell carcinoma, a lethal skin cell cancer. DeCaprio and Garcea compare and contrast these new human viruses and discuss how they might interact with their human host.

Auxin is perceived by a co-receptor complex that contains a TIR1 F-box protein and an Aux/IAA transcriptional repressor. The combinatorial diversity of auxin co-receptor complexes and their distinct spectra of affinities offer a means to tune plant cell sensitivity to a wide range of auxin concentrations.

The inhibitory protein SOCS3 plays a key part in hematopoiesis by regulating signaling induced by specific cytokines. The crystal structure of SOCS3 bound to JAK2 and a fragment of the interleulkin-6 receptor reveals how SOCS3 targets specific receptor–JAK complexes and how it exerts its inhibitory activity by blocking substrate binding.

Marco Sandri, Helge Amthor, Stefano Piccolo and colleagues show that BMP signaling is a key positive regulator of muscle hypertrophy. They further show that inhibiting BMP signaling causes muscle atrophy, abolishes the hypertrophic phenotype of myostatin knockout mice and exacerbates the effects of denervation and fasting.

Epidermolysis bullosa (EB) is a heterogeneous group of rare inherited genetic diseases characterized by mucocutaneous fragility and blister formation. This Primer describes the broad phenotypic spectrum of EB, including its potentially severe extracutaneous manifestations, as well as outlining the current mechanistic understanding and approaches to managing patients.

A number of angiogenic pathways have been implicated in urologic cancers, which could hold the key to developing antiangiogenic therapies against such tumors. Promoters and inhibitors of angiogenesis in tumors of the prostate, bladder and kidneys, and their use as either tumor markers or potential anticancer treatments, are reviewed in this article.

This study reports the structure of hRSV NS1, identifying unique regions that modulate host gene expression and contribute to inhibition of the IFN-I pathway and of dendritic cell maturation, pointing to new avenues of hRSV attenuation.

In May 2024, ‘Protein Degradation in Focus’, a special symposium aimed at bringing together scientists in the targeted protein degradation (TPD) field, was held in Dundee, UK. David Zollman and Kirsten McAulay report on the topics discussed and the exciting outlook for science in the TPD space.

CBF-β is shown to regulate the ability of HIV-1 to evade host restriction mediated by the deaminase APOBEC3.