Biology subjects

Fang, W.

Publications and source records attributed to Fang, W..

At least 55 records · Page 3Linked to original sources

bioRxiv2021

The Flowering Repressor SVP recruits the TOPLESS co-repressor to control flowering in chrysanthemum and Arabidopsis

Plant flowering time is a consequence of the perception of environmental and endogenous signals. The MCM1-AGAMOUSDEFICIENS-SRF-box (MADS-box) gene SHORT VEGETATIVE PHASE (SVP) is a pivotal repressor that negatively regulates the floral transition during the vegetative phase. The transcriptional corepressor TOPLESS (TPL) plays critical roles in many aspects of plant life. An interaction first identified between the second LXLXLX motif (LRLGLP) of CmSVP with CmTPL1-2, which can repress the expression of a key flowering factor CmFTL3 by binding its promotor CArG element in chrysanthemum. Genetic analysis suggested that the CmSVP-CmTPL1-2 transcriptional complex is a prerequisite for SVP to act as a floral repressor, which reduces CmFTL3 transcriptional activity. CmSVP rescued the phenotype of the svp-31 mutant in Arabidopsis, and overexpression of AtSVP or CmSVP in the Arabidopsis dominant negative mutation tpl-1 led to a loss-of-function in late flowering, which confirmed the highly conserved function of SVP in the two completely different species. Thus, we have validated a conserved machinery wherein SVP relies on TPL to inhibit flowering through the direct regulation of FT, which is more meaningful for the evolution of species and could be translated to high-quality cultivation and breeding of crops.

plant biology↗

bioRxiv2021

Acoustic and postural displays in a miniature and transparent teleost fish, Danionella dracula

Acoustic communication is widespread across vertebrates, including among fishes. We report robust acoustic displays during aggressive interactions for a laboratory colony of Danionella dracula, a relatively recently discovered miniature and transparent species of teleost fish closely related to zebrafish (Danio rerio). Males produce bursts of pulsatile, click-like sounds and a distinct postural display, extension of a hypertrophied lower jaw, during aggressive but not courtship interactions. Females lack a hypertrophied lower jaw and show no evidence of sound production or jaw extension in such contexts. Novel pairs of size-matched or -mismatched males were combined in resident-intruder assays where sound production and jaw extension could be linked to individuals. Resident males produce significantly more sound pulses and extend their jaw more often than intruders in both dyad contexts, and relatively larger males are significantly more sonic and exhibit more jaw extensions in size-mismatched pairs. The majority of highest sound producers in both contexts also show increased jaw extension during periods of heightened sonic activity. These studies firmly establish D. dracula as a sound-producing species that modulates both acoustic and postural displays during aggressive interactions based on either residency or body size, providing a foundation for further investigating the role of multimodal displays in a new model clade for neurogenomic studies of aggression, courtship, and other social interactions.

animal behavior and cognition↗

bioRxiv2021

Polypeptides IGF-1C and P24 synergistically promote osteogenic differentiation of bone marrow mesenchymal stem cells in vitro through the p38 and JNK signaling pathways

ObjectivesInsulin-like growth factor-1 (IGF-1) and bone morphogenetic protein 2 (BMP-2) both promote osteogenesis of bone marrow mesenchymal stem cells (BMSCs). IGF-1C, the C domain peptide of IGF-1, and P24, a BMP-2-derived peptide, both have similar biological activities as their parent growth factors. This study aimed to investigate the effects and their mechanisms of polypeptides IGF-1C and P24 on the osteogenic differentiation of BMSCs. MethodsThe optimum concentrations of IGF-IC and P24 were explored. The effects of the two polypeptides on the proliferation and osteogenic differentiation of BMSCs were examined using the Cell Counting Kit-8(CCK-8), Alkaline phosphatase (ALP) staining, ALP activity assay, alizarin red S staining, qPCR, and western blotting. In addition, specific pathway inhibitors were utilized to explore whether p38 and JNK pathways were involved in this process. ResultsThe optimal concentrations of action were both 50 g/ml. IGF-1C and P24 synergistically promoted the proliferation of BMSCs, increased ALP activity and the formation of calcified nodules and upregulated the mRNA and protein levels of osterix (Osx), runt-related transcription factor 2 (Runx2), and osteocalcin (Ocn), phosphorylation level of p38 and JNK proteins also improved. Inhibition of the pathways significantly reduced the activation of p38 and JNK, blocked the expression of Runx2 while inhibiting ALP activity and the formation of calcified nodules. ConclusionsThese findings suggest IGF-1C and P24 synergistically promote the osteogenesis of BMSCs through activation of p38 and JNK signal pathways.

cell biology↗

bioRxiv2021

ZHX2 Promotes HIF1α Oncogenic Signaling in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease, which warrants the critical need to identify new therapeutic targets. We show that Zinc Fingers And Homeoboxes 2 (ZHX2) is amplified or overexpressed in TNBC cell lines and patients. Functionally, depletion of ZHX2 inhibited TNBC cell growth and invasion in vitro, orthotopic tumor growth and spontaneous lung metastasis in vivo. Mechanistically, ZHX2 bound with hypoxia inducible factor (HIF) family members and positively regulated HIF1 activity in TNBC. Integrated ChIP-Seq and gene expression profiling demonstrated that ZHX2 co-occupied with HIF1 on transcriptionally active promoters marked by H3K4me3 and H3K27ac, thereby promoting gene expression. Furthermore, multiple residues (R491, R581 and R674) on ZHX2 are important in regulating its phenotype, which correspond with their roles on controlling HIF1 activity in TNBC cells. These studies establish that ZHX2 activates oncogenic HIF1 signaling, therefore serving as a potential therapeutic target for TNBC.

cancer biology↗

bioRxiv2021

Sequence Determinants of Human Junctophilin-2 Protein Nuclear Localization and Phase Separation

Junctophilin-2 (JPH2) was conventionally considered as a structural membrane binding protein. Recently, it was shown that proteolytically truncated mouse JPH2 variants are imported into nucleus to exert alternative functions. However, the intranuclear behaviors of human JPH2 (hJPH2) and underlying molecular determinants have not been explored. Here, we demonstrate that full-length hJPH2 is imported into nucleus in human cells by two nuclear localization signals (NLSs), including a newly discovered one at the C-terminus. Importantly, unlike the JPH2 N-terminal truncation which diffuses throughout the nucleus, full-length hJPH2 forms nuclear bodies behaving like liquid-liquid phase separated droplets that are separated from chromatin. The C-terminal transmembrane domain is required for the formation of hJPH2 droplets. Oxidation mimicking substitution of residues C678 and M679 augments the formation of hJPH2 nuclear droplets, suggesting nuclear hJPH2 liquid-liquid phase separation could be modulated by oxidative stress. Mutation A405D, which introduces a negatively charged residue into an intrinsic disordered region (IDR) of hJPH2, turns liquid-like droplets into amyloid-like aggregates. Depletion of an Alanine Rich Region in the IDR recapitulates the liquid-amyloid phase transition. The MORN repeat regions of hJPH2 encodes intrinsic tendency to form amyloid-like structure. Together, these data for the first time revealed the novel intrinsic properties of hJPH2 to form nuclear liquid droplets, and identified critical functional domains and residues encoding these properties. We propose that hJPH2 droplets could function as membrane-less organelles participating in nuclear regulatory processes.

biochemistry↗

bioRxiv2021

RNA-seq and differential expression analysis of the duck transcriptome: The effect of short-term cage-rearing

Ducks are an important source of meat and egg products for human beings. In China, duck breeding has gradually changed from the traditional floor-water combination system to multilayer cage breeding. Therefore, the present study collected the hypothalamus and pituitary of 113-day-old ducks after being caged for 3 days, in order to investigate the effect of cage-rearing on the birds. In addition, the same tissues (hypothalamus and pituitary) were collected from ducks raised in the floor-water combination system, for comparison. Thereafter, the transcriptomes were sequenced and the expression level of genes were compared. The results of sequencing analysis showed that a total of 506 and 342 genes were differentially expressed in the hypothalamus and pituitary, respectively. Additionally, the differentially expressed genes were mainly enriched in signaling pathways involved in processing environmental information, including ECM-receptor interaction, neuroactive ligand-receptor interaction and focal adhesion. The findings also showed that there was a change in the alternative splicing of genes when ducks were transferred into the cage rearing system. However, there was no difference in the expression of some genes although there was a change in the expression of the isoforms of these genes. The findings herein can therefore help in understanding the mechanisms underlying the effect of caging on waterfowl. The results also highlight the gene regulatory networks involved in animal responses to acute stress.

genetics↗

bioRxiv2021

Intracortical probe arrays with silicon backbone and microelectrodes on thin polyimide wings enable long-term stable recordings in vivo

ObjectiveRecording and stimulating neuronal activity across different brain regions requires interfacing at multiple sites using dedicated tools while tissue reactions at the recording sites often prevent their successful long-term application. This implies the technological challenge of developing complex probe geometries while keeping the overall footprint minimal, and of selecting materials compatible with neural tissue. While the potential of soft materials in reducing tissue response is uncontested, the implantation of these materials is often limited to reliably target neuronal structures across large brain volumes. ApproachWe report on the development of a new multi-electrode array exploiting the advantages of soft and stiff materials by combining 7-m-thin polyimide wings carrying platinum electrodes with a silicon backbone enabling a safe probe implantation. The probe fabrication applies microsystems technologies in combination with a temporal wafer fixation method for rear side processing, i.e., grinding and deep reactive ion etching, of slender probe shanks and electrode wings. The wing-type neural probes are chronically implanted into the entorhinal-hippocampal formation in the mouse for in vivo recordings of freely behaving animals. Main resultsProbes comprising the novel wing-type electrodes have been realized and characterized in view of their electrical performance and insertion capability. Chronic electrophysiological in vivo recordings of the entorhinal-hippocampal network in the mouse of up to 104 days demonstrated a stable yield of channels containing identifiable multi-unit and single-unit activity outperforming probes with electrodes residing on a Si backbone. SignificanceThe innovative fabrication process using a process compatible, temporary wafer bonding allowed to realize new Michigan style probe arrays. The wing-type probe design enables a precise probe insertion into brain tissue and long-term stable recordings of unit activity due to the application of a stable backbone and 7-m-thin probe wings provoking locally a minimal tissue response and protruding from the glial scare of the backbone.

neuroscience↗

bioRxiv2021

The entorhinal cortex modulates trace fear memory formation and neuroplasticity in the lateral amygdala via cholecystokinin

Although the neural circuitry underlying fear memory formation is important in fear-related mental disorders, it is incompletely understood. Here, we utilized trace fear conditioning to study the formation of trace fear memory. We identified the entorhinal cortex (EC) as a critical component of sensory signaling to the amygdala. Moreover, we used the loss of function and rescue experiments to demonstrate that release of the neuropeptide cholecystokinin (CCK) from the EC is required for trace fear memory formation. We discovered that CCK-positive neurons extend from the EC to the lateral nuclei of the amygdala (LA), and inhibition of CCK-dependent signaling in the EC prevented long-term potentiation of sensory signals to the LA and formation of trace fear memory. Altogether, we suggest a model where sensory stimuli trigger the release of CCK from EC neurons, which potentiates sensory signals to the LA, ultimately influencing neural plasticity and trace fear memory formation.

neuroscience↗

bioRxiv2021

Chromosome-level genome assembly of Acanthopagrus latus using PacBio and Hi-C technologies

The yellowfin seabream, Acanthopagrus latus, is widely distributed throughout the Indo-West Pacific. This fish is an ideal model species in which to study the mechanism of sex reversal since it exhibits a specific feature: sequential hermaphrodite. Here, we report a chromosome-scale assembly of the A. latus based on PacBio and Hi-C data. 22,485 protein-coding genes were annotated in whole genome level using transcriptome data. Taken together, this highly accurate, chromosome-level reference genome can provide a valuable resource to elucidate the mechanism of sex reversal for A. latus. Background & SummaryEvolution of sex, especially the evolution of different sexual systems, is a fascinating subject in evolutionary biology. The Sparidae, commonly known as seabreams or progies, is a family of fishes of the order Perciformes. And this family consist about 150 species in the world, which are mainly coastal fish1. Previous researchers mentioned that Sparidae is an ideal taxon to study the evolution history and adaptive significance of sexual systems, particularly for both types of sequential hermaphroditism, given that this group contains many protogyny, protandry and genochorist species2. The yellowfin seabream, Acanthopagrus latus is a protandry species which belongs to the Sparidae family. It is widely distributed in Indo-West Pacific area3. It has a great relevance for marine aquaculture and its biology is well focused on reproductive physiology and nutrition4. Interestingly, A. latus has a special gender feature is that it belongs to protandrous sexual system (initially as male and change later to female)5. Most of the past studies of A. latus mainly focused on the reproductive biology, population structure, aquaculture and taxonomy3,4,6-8. Although some sex reversal related genes were found in A. latus, the lack of genomic resources still limit us to elucidate the mechanism of sex reversal for this species.9,10. In addition, this lack was also limited the studies of evolution of sexual systems for Sparidae. In this study, long-read (PacBio SMRT) sequencing and Hi-C sequencing technologies were applied to construct a high quality reference genome for yellowfin seabream. This high-quality genome can provide a valuable resource to elucidate the mechanism of sex reversal for A. latus. Furthermore, this genome can also facilitate the studies of evolution of sexual systems for Sparidae.

genomics↗

bioRxiv2021

SNHG16 promotes cell proliferation and inhibits cell apoptosis via regulation of the miR-1303p/STARD9 axis in renal cell carcinoma

BackgroundRenal cell carcinoma (RCC) is a fatal malignant tumor with high morbidity. Numerous medical studies have suggested that long noncoding RNAs (lncRNAs) exert their biological function on various cancerous progresses. Herein, functions of lncRNA SNHG16 in RCC cells and the mechanism medicated by SNHG16 were investigated. MethodsThe expression levels of SNHG16 and its downstream genes in RCC cells and tissues were examined utilizing reverse transcription quantitative polymerase chain reaction analyses. Cell counting kit-8 and 5-Ethynyl-2-deoxyuridine assays were carried out to evaluate the proliferation of RCC cells, and flow cytometry analyses were employed to determine the apoptosis of RCC cells. Western blot analysis was applied to examine protein levels associated with cell proliferation and apoptosis. The combination between SNHG16 and miRNA as well as miRNA and its target gene were explored by luciferase reporter, RNA pull down, and RNA immunoprecipitation assays. ResultsThe significant upregulation of SNHG16 was observed in RCC tissues and cells. SNHG16 downregulation inhibited the proliferation and promoted the apoptosis of RCC cells. In addition, SNHG16 served as a competing endogenous RNA for miR-1301-3p, and STARD9 was a target gene of miR-1301-3p in RCC cells. SNHG16 upregulated STARD9 expression by binding with miR-1301-3p in RCC cells. Rescue assays validated that SNHG16 promoted RCC cell promotion and induced RCC cell apoptosis by upregulating STARD9 expression. ConclusionsSNHG16 promotes RCC cell proliferation and suppresses RCC cell apoptosis via interaction with miR-1301-3p to upregulate STARD9 expression in RCC cells.

cell biology↗

bioRxiv2021

The nonstructural protein 5 of coronaviruses antagonizes GSDMD-mediated pyroptosis by cleaving and inactivating its pore-forming p30 fragment

Coronaviruses (CoV) are a family of RNA viruses that typically cause respiratory, enteric and hepatic diseases in animals and humans. Here, we used porcine epidemic diarrhea virus (PEDV) as a model of coronaviruses (CoVs) to illustrate the reciprocal regulation between CoVs infection and pyroptosis. For the first time, we clarified the molecular mechanism of porcine Gasdermin D (pGSDMD)-mediated pyroptosis and demonstrated that amino acids T239 and F240 within pGSDMD-p30 are critical for pyroptosis. Furthermore, 3C-like protease Nsp5 from SARS-CoV-2, MERS-CoV, PDCoV and PEDV can cleave human/porcine GSDMD at the Q193-G194 junction upstream of the caspase-1 cleavage site to produce two fragments which fail to trigger pyroptosis or inhibit viral replication. Thus, we provide clear evidence that coronoviruses may utilize viral Nsp5-GSDMD pathway to help their host cells escaping from pyroptosis, protecting the replication of the virus during the initial period, which suggest an important strategy for coronoviruses infection and sustain.

microbiology↗

bioRxiv2020

A negative feedback model to explain regulation of SARS-CoV-2 replication and transcription

BackgroundCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although a preliminary understanding of the replication and transcription mechanisms of SARS-CoV-2 has recently emerged, their regulation remains unclear. ResultsBased on reanalysis of public data, we propose a negative feedback model to explain the regulation of replication and transcription in--but not limited to--SARS-CoV-2. The key step leading to new discoveries was the identification of the cleavage sites of nsp15--an RNA uridylate-specific endoribonuclease, encoded by CoVs. According to this model, nsp15 regulates the synthesis of subgenomic RNAs (sgRNAs) and genomic RNAs (gRNAs) by cleaving transcription regulatory sequences in the body. The expression level of nsp15 determines the relative proportions of sgRNAs and gRNAs, which in turn change the expression level of nps15 to reach equilibrium between the replication and transcription of CoVs. ConclusionsThe replication and transcription of CoVs are regulated by a negative feedback mechanism that influences the persistence of CoVs in hosts. Our findings enrich fundamental knowledge in the field of gene expression and its regulation, and provide new clues for future studies. One important clue is that nsp15 may be an important and ideal target for the development of drugs (e.g. uridine derivatives) against CoVs.

bioinformatics↗

bioRxiv2020

Pan-genome analyses of peach and its wild relatives provide insights into the genetics of disease resistance and species adaptation

As a foundation to understand the molecular mechanisms of peach evolution and high-altitude adaptation, we performed de novo genome assembling of four wild relatives of P. persica, P. mira, P. kansuensis, P. davidiana and P. ferganensis. Through comparative genomic analysis, abundant genetic variations were identified in four wild species when compared to P. persica. Among them, a deletion, located at the promoter of Prupe.2G053600 in P. kansuensis, was validated to regulate the resistance to nematode. Next, a pan-genome was constructed which comprised 15,216 core gene families among four wild peaches and P. perisca. We identified the expanded and contracted gene families in different species and investigated their roles during peach evolution. Our results indicated that P. mira was the primitive ancestor of cultivated peach, and peach evolution was non-linear and a cross event might have occurred between P. mira and P. dulcis during the process. Combined with the selective sweeps identified using accessions of P. mira originating from different altitude regions, we proposed that nitrogen recovery was essential for high-altitude adaptation of P. mira through increasing its resistance to low temperature. The pan-genome constructed in our study provides a valuable resource for developing elite cultivars, studying the peach evolution, and characterizing the high-altitude adaptation in perennial crops.

plant biology↗

bioRxiv2020

Genomic analyses provide insights into peach local adaptation and responses to climate change

The environment has constantly shaped plant genomes, but the genetic bases underlying how plants adapt to environmental influences remain largely unknown. We constructed a high-density genomic variation map by re-sequencing genomes of 263 geographically representative peach landraces and wild relatives. A combination of whole-genome selection scans and genome-wide environmental association studies (GWEAS) was performed to reveal the genomic bases of peach local adaptation to diverse climates comprehensively. A total of 2,092 selective sweeps that underlie local adaptation to both mild and extreme climates were identified, including 339 sweeps conferring genomic pattern of adaptation to high altitudes. Using GWEAS, a total of 3,496 genomic loci strongly associated with 51 specific environmental variables were detected. The molecular mechanism underlying adaptive evolution of high drought, strong UV-B, cold hardiness, sugar content, flesh color, and bloom date were revealed. Finally, based on 30 years of observation, a candidate gene associated with bloom date advance, representing peach responses to global warming, was identified. Collectively, our study provides insights into molecular bases of how environments have shaped peach genomes by natural selection and adds valuable genome resources and candidate genes for future studies on evolutionary genetics, adaptation to climate changes, and future breeding.

genomics↗

bioRxiv2020

Targeting a critical step in fungal hexosamine biosynthesis

Aspergillus fumigatus is a human opportunistic fungal pathogen with a cell wall that protects it from the extracellular environment. Chitin, an essential cell wall component, is synthesised from UDP-GlcNAc that is produced by the hexosamine biosynthetic pathway. Here, we provide genetic and chemical evidence that glucosamine 6-phosphate N-acetyltransferase (Gna1), a key enzyme in this pathway, is an exploitable antifungal drug target. Deletion of GNA1 results in loss of viability and disruption of the cell wall, phenotypes that can be rescued by the product of the enzyme. In a murine model of aspergillosis, the{Delta} gna1 mutant strain attenuates virulence. Using a fragment-based approach, we discovered a small heterocyclic scaffold that binds proximal to the active site and can be optimised to a selective sub-micromolar binder. Taken together, we have provided genetic, structural and chemical evidence for Gna1 as an antifungal target in Aspergillus fumigatus.

microbiology↗

bioRxiv2019

Identification and characterization of cis-regulatory elements for photoreceptor type-specific transcription in zebrafish

Tissue-specific or cell type-specific transcription of protein-coding genes is controlled by both trans-regulatory elements (TREs) and cis-regulatory elements (CREs). However, it is challenging to identify TREs and CREs, which are unknown for most genes. Here, we describe a protocol for identifying two types of transcription-activating CREs--core promoters and enhancers--of zebrafish photoreceptor type-specific genes. This protocol is composed of three phases: bioinformatic prediction, experimental validation, and characterization of the CREs. To better illustrate the principles and logic of this protocol, we exemplify it with the discovery of the core promoter and enhancer of the mpp5b apical polarity gene (also known as ponli), whose red, green, and blue (RGB) cone-specific transcription requires its enhancer, a member of the rainbow enhancer family. While exemplified with an RGB cone-specific gene, this protocol is general and can be used to identify the core promoters and enhancers of other protein-coding genes.

developmental biology↗

bioRxiv2019

Impact of Prior Cancer on Outcomes in Nasopharyngeal Carcinoma

BackgroundPrior cancer is a common exclusion criterion in nasopharyngeal carcinoma (NPC) trials. However, whether a prior cancer diagnosis affects trial outcomes is still unknown. We aimed to determine the impact of prior cancer on survival in NPC. MethodsWe identified patients diagnosed with NPC between 2004 and 2009 in the Surveillance, Epidemiology, and End Results (SEER) database. Variables were compared by chi-squared test and t-test as appropriate. Propensity score-adjusted Kaplan-Meier methods and Cox proportional hazard models were used to evaluate the impact of prior cancer on overall survival (OS). ResultsAmong 3,131 eligible NPC patients, 349 (11.15%) patients had a history of prior cancer. The Kaplan-Meier curves did not show a statistically significantly different OS (p=0.19). Subgroup analyses stratified by timing of prior cancer and AJCC TNM stage of index cancer displayed the same tendency, prior cancer didnt adversely affect OS compared with patients without prior cancer (p>0.05). Furthermore, in propensity score-adjusted COX models analysis, patients with prior cancer had the same/non-inferior OS (hazard ratio [HR] = 1.12, 95% confidence interval= 0.88 to 1.42). ConclusionsAmong patients with nasopharyngeal carcinoma, prior cancer does not convey an adverse effect on clinical outcomes, regardless of the timing of prior cancer and AJCC TNM stage of index cancer. Broader inclusion trial criteria could be adopted in nasopharyngeal carcinoma patients with a history of prior cancer. However, further studies are still needed to confirm.

epidemiology↗

bioRxiv2018

UBE2G1 Governs the Destruction of Cereblon Neomorphic Substrates

The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide as well as the novel cereblon modulating agents (CMs) including CC-122, CC-220 and cereblon-based proteolysis-targeting chimaeras (PROTACs) repurpose the Cul4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with an E1 ubiquitin-activating enzyme and E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the polyubiquitination of CRL4CRBN neomorphic substrates in a cereblon- and CM-dependent manner via a sequential ubiquitination mechanism: UBE2D3 transforms the neomorphic substrates into mono-ubiquitinated forms, upon which UBE2G1 catalyzes K48-linked polyubiquitin chain extension. Blockade of UBE2G1 diminishes the ubiquitination and degradation of neomorphic substrates, and consequent antitumor activities elicited by all tested CMs. For example, UBE2G1 inactivation significantly attenuated the degradation of myeloma survival factors IKZF1 and IKZF3 induced by lenalidomide and pomalidomide, hence conferring drug resistance. UBE2G1-deficient myeloma cells, however, remained sensitive to a more potent IKZF1/3 degrader CC-220. Collectively, these findings suggest that loss of UBE2G1 activity might be a resistance mechanism to drugs that hijack the CRL4CRBN to eliminate disease-driving proteins, and that this resistance mechanism can be overcome by next-generation CMs that destroy the same targeted protein more effectively.

molecular biology↗