Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential.

Elf1 promotes Rad26's interaction with lesion-arrested Pol II for transcription-coupled repair.

Transcription-coupled nucleotide excision repair (TC-NER) is a highly conserved DNA repair pathway that removes bulky lesions in the transcribed genome. Cockayne syndrome B protein (CSB), or its yeast ortholog Rad26, has been known for decades to play important roles in the lesion-recognition steps of TC-NER. Another conserved protein ELOF1, or its yeast ortholog Elf1, was recently identified as a core transcription-coupled repair factor. How Rad26 distinguishes between RNA polymerase II (Pol II) stalled at a DNA lesion or other obstacles and what role Elf1 plays in this process remains unknown. Here, we present cryo-EM structures of Pol II-Rad26 complexes stalled at different obstacles that show that Rad26 uses a common mechanism to recognize a stalled Pol II, with additional interactions when Pol II is arrested at a lesion. A cryo-EM structure of lesion-arrested Pol II-Rad26 bound to Elf1 revealed that Elf1 induces further interactions between Rad26 and a lesion-arrested Pol II. Biochemical and genetic data support the importance of the interplay between Elf1 and Rad26 in TC-NER initiation. Together, our results provide important mechanistic insights into how two conserved transcription-coupled repair factors, Rad26/CSB and Elf1/ELOF1, work together at the initial lesion recognition steps of transcription-coupled repair.

Interplay of the Tfb1 pleckstrin homology domain with Rad2 and Rad4 in transcription coupled and global genomic nucleotide excision repair.

Transcription-coupled repair (TCR) and global genomic repair (GGR) are two subpathways of nucleotide excision repair (NER). The TFIIH subunit Tfb1 contains a Pleckstrin homology domain (PHD), which was shown to interact with one PHD-binding segment (PB) of Rad4 and two PHD-binding segments (PB1 and PB2) of Rad2 in vitro. Whether and how the different Rad2 and Rad4 PBs interact with the same Tfb1 PHD, and whether and how they affect TCR and GGR within the cell remain mysterious. We found that Rad4 PB constitutively interacts with Tfb1 PHD, and the two proteins may function within one module for damage recognition in TCR and GGR. Rad2 PB1 protects Tfb1 from degradation and interacts with Tfb1 PHD at a basal level, presumably within transcription preinitiation complexes when NER is inactive. During a late step of NER, the interaction between Rad2 PB1 and Tfb1 PHD augments, enabling efficient TCR and GGR. Rather than interacting with Tfb1 PHD, Rad2 PB2 constrains the basal interaction between Rad2 PB1 and Tfb1 PHD, thereby weakening the protection of Tfb1 from degradation and enabling rapid augmentation of their interactions within TCR and GGR complexes. Our results shed new light on NER mechanisms.

Proteomics Profiling Reveals the Molecular Signatures and Potential Therapeutic Targets of Human Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC), a malignant tumor distinctly characterized by ethnic and geographic distribution, is highly prevalent in Southern China and Southeast Asia. However, the molecular mechanisms of NPC have not been fully revealed at the proteomic level. In this study, 30 primary NPC samples and 22 normal nasopharyngeal epithelial tissues were collected for proteomics analysis, and a relatively complete proteomics landscape of NPC was depicted for the first time. By combining differential expression analysis, differential co-expression analysis, and network analysis, potential biomarkers and therapeutic targets were identified. Some identified targets were verified by biological experiments. We found that 17-AAG, a specific inhibitor of the identified target heat shock protein 90 (HSP90), could be a potential therapeutic drug for NPC. Finally, consensus clustering identified two NPC subtypes with specific molecular features. The subtypes and the related molecules were verified by an independent data set and may have different progression-free survival. The results of this study provide a comprehensive understanding of the proteomics molecular signatures of NPC and provide new perspectives and inspiration for prognostic determination and treatment of NPC.

How much does TRPV1 deviate from an ideal MWC-type protein?

Many ion channels are known to behave as an allosteric protein, coupling environmental stimuli captured by specialized sensing domains to the opening of a central pore. The classic Monod-Wyman-Changeux (MWC) model, originally proposed to describe binding of gas molecules to hemoglobin, has been widely used as a framework for analyzing ion channel gating. Here, we address the issue of how accurately the MWC model predicts activation of the capsaicin receptor TRPV1 by vanilloids. Taking advantage of a concatemeric design that makes it possible to lock TRPV1 in states with zero to four bound vanilloid molecules, we showed quantitatively that the overall gating behavior is satisfactorily predicted by the MWC model. There is, however, a small yet detectable subunit position effect: ligand binding to two kitty-corner subunits is 0.3-0.4 kcal/mol more effective in inducing opening than binding to two neighbor subunits. This difference-less than 10% of the overall energetic contribution from ligand binding-might be due to the restriction on subunit arrangement imposed by the planar membrane; if this is the case, then the position effect is not expected in hemoglobin, in which each subunit is related equivalently to all the other subunits.

Rpb7 represses transcription-coupled nucleotide excision repair.

Transcription-coupled repair (TCR) is a subpathway of nucleotide excision repair (NER) that is regulated by multiple facilitators, such as Rad26, and repressors, such as Rpb4 and Spt4/Spt5. How these factors interplay with each other and with core RNA polymerase II (RNAPII) remains largely unknown. In this study, we identified Rpb7, an essential RNAPII subunit, as another TCR repressor and characterized its repression of TCR in the AGP2, RPB2, and YEF3 genes, which are transcribed at low, moderate, and high rates, respectively. The Rpb7 region that interacts with the KOW3 domain of Spt5 represses TCR largely through the same common mechanism as Spt4/Spt5, as mutations in this region mildly enhance the derepression of TCR by spt4Δ only in the YEF3 gene but not in the AGP2 or RPB2 gene. The Rpb7 regions that interact with Rpb4 and/or the core RNAPII repress TCR largely independently of Spt4/Spt5, as mutations in these regions synergistically enhance the derepression of TCR by spt4Δ in all the genes analyzed. The Rpb7 regions that interact with Rpb4 and/or the core RNAPII may also play positive roles in other (non-NER) DNA damage repair and/or tolerance mechanisms, as mutations in these regions can cause UV sensitivity that cannot be attributed to derepression of TCR. Our study reveals a novel function of Rpb7 in TCR regulation and suggests that this RNAPII subunit may have broader roles in DNA damage response beyond its known function in transcription.

The capsaicin binding affinity of wildtype and mutant TRPV1 ion channels.

Vanilloids such as capsaicin and resiniferatoxin are highly selective and potent activators for transient receptor potential vanilloid subfamily, member 1, a nociceptor for heat and pain perception. However, the intrinsic vanilloid binding affinity, key for understanding transient receptor potential vanilloid subfamily, member 1 function, remains unknown despite intensive investigations by electrophysiological, structural, and computational methods. In this study, we determined capsaicin binding affinity under physiological conditions by isolating individual binding steps to each subunit with concatemers. We estimated the capsaicin association constant of a wildtype subunit to be in the order of 106 M-1 and that of the Y511A mutant subunit to be a hundred times lower, in the order of 104 M-1. The Y511A mutation, located at the entrance of the vanilloid binding pocket, reduces binding affinity without a noticeable effect on activation gating. We further affirmed that there is little cooperativity between vanilloid binding steps. Models based on independent binding and equally cooperative subunit gating can accurately describe capsaicin activation.

Opening of capsaicin receptor TRPV1 is stabilized equally by its four subunits.

Capsaicin receptor TRPV1 is a nociceptor for vanilloid molecules, such as capsaicin and resiniferatoxin (RTX). Even though cryo-EM structures of TRPV1 in complex with these molecules are available, how their binding energetically favors the open conformation is not known. Here, we report an approach to control the number of bound RTX molecules (0-4) in functional rat TRPV1. The approach allowed direct measurements of each of the intermediate open states under equilibrium conditions at both macroscopic and single-molecule levels. We found that RTX binding to each of the four subunits contributes virtually the same activation energy, which we estimated to be 1.70 to 1.86 kcal/mol and found to arise predominately from destabilizing the closed conformation. We further showed that sequential bindings of RTX increase open probability without altering single-channel conductance, confirming that there is likely a single open-pore conformation for TRPV1 activated by RTX.

Root-to-shoot signaling positively mediates source-sink relation in late growth stages in diploid and tetraploid wheat.

Non-hydraulic root source signaling (nHRS) is a unique positive response to soil drying in the regulation of plant growth and development. However, it is unclear how the nHRS mediates the tradeoff between source and sink at the late growth stages and its adaptive mechanisms in primitive wheat. To address this issue, a root-splitting design was made by inserting solid partition in the middle of the pot culture to induce the occurrence of nHRS using four wheat cultivars (MO1 and MO4, diploid; DM22 and DM31, tetraploid) as materials. Three water treatments were designed as 1) both halves watered (CK), 2) holistic root system watered then droughted (FS), 3) one-half of the root system watered and half droughted (PS). FS and PS were designed to compare the role of the full root system and split root system to induce nHRS. Leaves samples were collected during booting and anthesis to compare the role of nHRS at both growth stages. The data indicated that under PS treatment, ABA concentration was significantly higher than FS and CK, demonstrating the induction of nHRS in split root design and nHRS decreased cytokinin (ZR) levels, particularly in the PS treatment. Soluble sugar and proline accumulation were higher in the anthesis stage as compared to the booting stage. POD activity was higher at anthesis, while CAT was higher at the booting stage. Increased ABA (nHRS) correlated with source-sink relationships and metabolic rate (i.e., leaf) connecting other stress signals. Biomass density showed superior resource acquisition and utilization capabilities in both FS and PS treatment as compared to CK in all plants. Our findings indicate that nHRS-induced alterations in phytohormones and their effect on source-sink relations were allied with the growth stages in primitive wheat.

Inhibition of autophagy enhances the anticancer effect of Schisandrin B on head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is among the most common malignant tumors worldwide and has a poor prognosis. Autophagy regulation has been proposed as a possible treatment option for HNSCC. Schisandrin B (Sch B) exerts anticancer effects by regulating apoptosis and autophagy, but the anticancer effect of Sch B in HNSCC remains unclear. This study aimed to investigate the effects of Sch B on human Cal27 HNSCC cells and to further reveal its potential regulatory mechanisms. The anticancer effect of Sch B was evaluated in vitro by flow cytometry, clonogenic assays, and Western blot analysis. The regulatory mechanism of Sch B-induced apoptosis and autophagy was further explored by polymerase chain reaction, luciferase assay, and reactive oxygen species (ROS) detection. The results showed that Sch B significantly induced apoptosis and autophagy in Cal27 cells and that inhibition of autophagy enhanced the apoptotic effect of Sch B on Cal27 cells. Additionally, Sch B-activated autophagy in Cal27 cells was dependent on the nuclear factor-kappa B (NF-κB) pathway, and ROS acted as a regulator of the NF-B pathway. N-acetylcysteine, a scavenger of ROS, inhibited Sch B-dependent autophagy via the NF-κB pathway. Based on the results, Sch B is a potential therapeutic agent for HNSCC and activates the NF-κB pathway by increasing ROS production, which subsequently promotes autophagy in HNSCC cells. Therefore, the strategy of enhancing the anticancer effect of Sch B by inhibiting autophagy deserves further attention.

Manganese-derived biomaterials for tumor diagnosis and therapy.

Manganese (Mn) is widely recognized owing to its low cost, non-toxic nature, and versatile oxidation states, leading to the emergence of various Mn-based nanomaterials with applications across diverse fields, particularly in tumor diagnosis and therapy. Systematic reviews specifically addressing the tumor diagnosis and therapy aspects of Mn-derived biomaterials are lacking. This review comprehensively explores the physicochemical characteristics and synthesis methods of Mn-derived biomaterials, emphasizing their role in tumor diagnostics, including magnetic resonance imaging, photoacoustic and photothermal imaging, ultrasound imaging, multimodal imaging, and biodetection. Moreover, the advantages of Mn-based materials in tumor treatment applications are discussed, including drug delivery, tumor microenvironment regulation, synergistic photothermal, photodynamic, and chemodynamic therapies, tumor immunotherapy, and imaging-guided therapy. The review concludes by providing insights into the current landscape and future directions for Mn-driven advancements in the field, serving as a comprehensive resource for researchers and clinicians.

Exosome-based delivery strategies for tumor therapy: an update on modification, loading, and clinical application.

Malignancy is a major public health problem and among the leading lethal diseases worldwide. Although the current tumor treatment methods have therapeutic effect to a certain extent, they still have some shortcomings such as poor water solubility, short half-life, local and systemic toxicity. Therefore, how to deliver therapeutic agent so as to realize safe and effective anti-tumor therapy become a problem urgently to be solved in this field. As a medium of information exchange and material transport between cells, exosomes are considered to be a promising drug delivery carrier due to their nano-size, good biocompatibility, natural targeting, and easy modification. In this review, we summarize recent advances in the isolation, identification, drug loading, and modification of exosomes as drug carriers for tumor therapy alongside their application in tumor therapy. Basic knowledge of exosomes, such as their biogenesis, sources, and characterization methods, is also introduced herein. In addition, challenges related to the use of exosomes as drug delivery vehicles are discussed, along with future trends. This review provides a scientific basis for the application of exosome delivery systems in oncological therapy.

Effects of oropharyngeal exercises on CPAP compliance: A prospective intervention study.

PURPOSE: To investigate the effects of oropharyngeal exercise on continuous positive airway pressure (CPAP) compliance in patients with moderate to severe obstructive sleep apnea over a period of 6 months. MATERIALS AND METHODS: This study was conducted as a prospective, observational, and interventional investigation. A total of 70 patients with moderate to severe obstructive sleep apnea were randomly assigned to either the oropharyngeal exercise group (n = 44) or the sham-therapy group (n = 26). The compliance of the enrolled patients with CPAP therapy was assessed at baseline, 3-month follow-up and 6-month follow-up. Objective sleep data, questionnaire and CPAP use time were collected over a half-year period (i.e., baseline, 6 months, and 12 months). RESULTS: The study found that the average use time of CPAP within one month was significantly longer in the oropharyngeal exercises group compared to the sham-therapy group at the 3-month assessment (5.5 ± 1.2 vs 4.8 ± 1.3 h per night; p=0.030), and much significantly longer at 6-months assessment (6.0 ± 1.4 vs 4.9 ± 1.3 h per night; p=0.001). Furthermore, the average use time of CPAP increased over time, with the oropharyngeal exercises group exhibiting a more pronounced growth from baseline to the six-month follow-up (4.8 ± 1.0 h per night to 6.0 ± 1.3 h per night, p < 0.001) compared to the sham-therapy group (4.8 ± 1.3 h per night to 4.9 ± 1.3 h per night, p=0.952). Additionally, the oropharyngeal exercise group demonstrated an improvement in the Epworth sleepiness scale compared to the sham-therapy group at the 3-month follow-up (6.0 ± 2.0 vs 8.8 ± 3.2; p < 0.001), as well as decreased significantly at 6-month follow-up (p = 0.032). CONCLUSIONS: CPAP adherence can be improved with oropharyngeal exercises therapy among moderate to severe OSA patients. Notably, the average duration of CPAP usage and reduction in daytime sleepiness were maintained even after six months of oropharyngeal exercise therapy.

Optical Control of High-Harmonic Generation at the Atomic Thickness.

High-harmonic generation (HHG), an extreme nonlinear optical phenomenon beyond the perturbation regime, is of great significance for various potential applications, such as high-energy ultrashort pulse generation with outstanding spatiotemporal coherence. However, efficient active control of HHG is still challenging due to the weak light-matter interaction displayed by currently known materials. Here, we demonstrate optically controlled HHG in monolayer semiconductors via the engineering of interband polarization. We find that HHG can be efficiently controlled in the excitonic spectral region with modulation depths up to 95% and ultrafast response speeds of several picoseconds. Quantitative time-domain theory of the nonlinear optical susceptibilities in monolayer semiconductors further corroborates these experimental observations. Our demonstration not only offers an in-depth understanding of HHG but also provides an effective approach toward active optical devices for strong-field physics and extreme nonlinear optics.

The fate of antibiotic resistance genes in the coastal lagoon with multiple functional zones.

Coastal lagoons provide many important services to human society, but their year-round use for aquaculture introduces large amounts of sewage. The contamination of antibiotic resistance genes (ARGs) is therefore of great concern. In this study, 50 ARGs subtypes, two integrase genes (intl1, intl2), and 16S rRNA genes were detected by high-throughput quantitative PCR, and standard curves of all target genes were prepared for quantification. The occurrence and distribution of ARGs in a typical coastal lagoon (XinCun lagoon, China) were comprehensively explored. We detected 44 and 38 subtypes of ARGs in the water and sediment, respectively, and discuss the various factors influencing the fate of ARGs in the coastal lagoon. Macrolides-lincosamides-streptogramins B was the primary ARG type, and macB was the predominant subtype. Antibiotic efflux and antibiotic inactivation were the main ARG resistance mechanisms. The XinCun lagoon was divided into eight functional zones. The ARGs showed a distinct spatial distribution owing to the influence of microbial biomass and anthropogenic activity in different functional zones. Fishing rafts, abandoned fish ponds, the town sewage zone, and mangrove wetlands provided a large quantity of ARGs to the XinCun lagoon. Nutrients and heavy metals also significantly correlated with the fate of the ARGs, especially NO2--N and Cu, which cannot be ignored. It is noteworthy that lagoon-barrier systems coupled with persistent pollutant inputs result in coastal lagoons acting as a "buffer pool" for ARGs, which can then accumulate and threaten the offshore environment.

R gene triplication confers European fodder turnip with improved clubroot resistance.

Clubroot is one of the most important diseases for many important cruciferous vegetables and oilseed crops worldwide. Different clubroot resistance (CR) loci have been identified from only limited species in Brassica, making it difficult to compare and utilize these loci. European fodder turnip ECD04 is considered one of the most valuable resources for CR breeding. To explore the genetic and evolutionary basis of CR in ECD04, we sequenced the genome of ECD04 using de novo assembly and identified 978 candidate R genes. Subsequently, the 28 published CR loci were physically mapped to 15 loci in the ECD04 genome, including 62 candidate CR genes. Among them, two CR genes, CRA3.7.1 and CRA8.2.4, were functionally validated. Phylogenetic analysis revealed that CRA3.7.1 and CRA8.2.4 originated from a common ancestor before the whole-genome triplication (WGT) event. In clubroot susceptible Brassica species, CR-gene homologues were affected by transposable element (TE) insertion, resulting in the loss of CR function. It can be concluded that the current functional CR genes in Brassica rapa and non-functional CR genes in other Brassica species were derived from a common ancestral gene before WGT. Finally, a hypothesis for CR gene evolution is proposed for further discussion.

Broadband Plasmon-Enhanced Four-Wave Mixing in Monolayer MoS2.

Two-dimensional transition-metal dichalcogenide monolayers have remarkably large optical nonlinearity. However, the nonlinear optical conversion efficiency in monolayer transition-metal dichalcogenides is typically low due to small light-matter interaction length at the atomic thickness, which significantly obstructs their applications. Here, for the first time, we report broadband (up to ∼150 nm) enhancement of optical nonlinearity in monolayer MoS2 with plasmonic structures. Substantial enhancement of four-wave mixing is demonstrated with the enhancement factor up to three orders of magnitude for broadband frequency conversion, covering the major visible spectral region. The equivalent third-order nonlinearity of the hybrid MoS2-plasmonic structure is in the order of 10-17 m2/V2, far superior (∼10-100-times larger) to the widely used conventional bulk materials (e.g., LiNbO3, BBO) and nanomaterials (e.g., gold nanofilms). Such a considerable and broadband enhancement arises from the strongly confined electric field in the plasmonic structure, promising for numerous nonlinear photonic applications of two-dimensional materials.

Single-particle studies on plasmon enhanced photoluminescence of monolayer MoS2 by gold nanoparticles of different shapes.

Plasmon-exciton interactions between noble metal nanostructures and two-dimensional transition metal dichalcogenides have drawn great interest due to their significantly enhanced optical properties. Plasmon resonance of noble metal nanoparticles and plasmon-exciton interactions are strongly dependent on the particle morphology. Single-particle spectroscopic studies can overcome the ensemble average effects of sample inhomogeneity to unambiguously reveal the effects of the particle morphology. In this work, plasmon modulated emission of MoS2 in various plasmon-MoS2 hybrid structures has been studied on the single-particle level. Gold (Au) nanoantennas of different shapes including nanosphere, nanorod, nanocube, and nanotriangle with similar overall dimensions, which have different sharp tips and contact areas with MoS2, have been chosen to explore the particle shape effects. Different extent of enhancement in photoluminescence (PL) of MoS2 was observed for Au nanoantennas of different shapes. It was found that Au nanotriangles gave the highest enhancement factor, while Au nanospheres gave the lowest enhancement factor. The numerical simulation results show that the dominant contribution arises from an increased quantum yield, while enhanced excitation efficiency just plays a minor role. The quantum yield enhancement is affected by both the sharp tips and contact mode of the Au nanoantenna with MoS2. Polarization of the MoS2 emission was also found to be modulated by the plasmon mode of the Au nanoantenna. These single-particle spectroscopic studies allow us to unambiguously reveal the effects of the particle morphology on plasmon enhanced PL in these nanohybrids to provide a better understanding of the plasmon-exciton interactions.

Histone H4 H75E mutation attenuates global genomic and Rad26-independent transcription-coupled nucleotide excision repair.

Nucleotide excision repair (NER) consists of global genomic NER (GG-NER) and transcription coupled NER (TC-NER) subpathways. In eukaryotic cells, genomic DNA is wrapped around histone octamers (an H3-H4 tetramer and two H2A-H2B dimers) to form nucleosomes, which are well known to profoundly inhibit the access of NER proteins. Through unbiased screening of histone H4 residues in the nucleosomal LRS (loss of ribosomal DNA-silencing) domain, we identified 24 mutations that enhance or decrease UV sensitivity of Saccharomyces cerevisiae cells. The histone H4 H75E mutation, which is largely embedded in the nucleosome and interacts with histone H2B, significantly attenuates GG-NER and Rad26-independent TC-NER but does not affect TC-NER in the presence of Rad26. All the other histone H4 mutations, except for T73F and T73Y that mildly attenuate GG-NER, do not substantially affect GG-NER or TC-NER. The attenuation of GG-NER and Rad26-independent TC-NER by the H4H75E mutation is not due to decreased chromatin accessibility, impaired methylation of histone H3 K79 that is at the center of the LRS domain, or lowered expression of NER proteins. Instead, the attenuation is at least in part due to impaired recruitment of Rad4, the key lesion recognition and verification protein, to chromatin following induction of DNA lesions.

Genome-wide screening identifies novel genes and biological processes implicated in cisplatin resistance.

Cisplatin-based chemotherapeutic regimens are frequently used for treatments of solid tumors. However, tumor cells may have inherent or acquired cisplatin resistance, and the underlying mechanisms are largely unknown. We performed genome-wide screening of genes implicated in cisplatin resistance in A375 human melanoma cells. A substantial fraction of genes whose disruptions cause cisplatin sensitivity or resistance overlap with those whose disruptions lead to increased or decreased cell growth, respectively. Protein translation, mitochondrial respiratory chain complex assembly, signal recognition particle-dependent cotranslational protein targeting to membrane, and mRNA catabolic processes are the top biologic processes responsible for cisplatin sensitivity. In contrast, proteasome-mediated ubiquitin-dependent protein catabolic process, negative regulations of cellular catabolic process, and regulation of cellular protein localization are the top biologic processes responsible for cisplatin resistance. ZNRF3, a ubiquitin ligase known to be a target and negative feedback regulator of Wnt-ß-catenin signaling, enhances cisplatin resistance in normal and melanoma cells independently of ß-catenin. Ariadne-1 homolog (ARIH1), another ubiquitin ligase, also enhances cisplatin resistance in normal and melanoma cells. By regulating ARIH1, neurofibromin 2, a tumor suppressor, enhances cisplatin resistance in melanoma but not normal cells. Our results shed new lights on cisplatin resistance mechanisms and may be useful for development of cisplatin-related treatment strategies.-Ko, T., Li, S. Genome-wide screening identifies novel genes and biological processes implicated in cisplatin resistance.