Stearate-derived very long-chain fatty acids are indispensable to tumor growth.

Reprogramming of lipid metabolism is emerging as a hallmark of cancer, yet involvement of specific fatty acids (FA) species and related enzymes in tumorigenesis remains unclear. While previous studies have focused on involvement of long-chain fatty acids (LCFAs) including palmitate in cancer, little attention has been paid to the role of very long-chain fatty acids (VLCFAs). Here, we show that depletion of acetyl-CoA carboxylase (ACC1), a critical enzyme involved in the biosynthesis of fatty acids, inhibits both de novo synthesis and elongation of VLCFAs in human cancer cells. ACC1 depletion markedly reduces cellular VLCFA but only marginally influences LCFA levels, including palmitate that can be nutritionally available. Therefore, tumor growth is specifically susceptible to regulation of VLCFAs. We further demonstrate that VLCFA deficiency results in a significant decrease in ceramides as well as downstream glucosylceramides and sphingomyelins, which impairs mitochondrial morphology and renders cancer cells sensitive to oxidative stress and cell death. Taken together, our study highlights that VLCFAs are selectively required for cancer cell survival and reveals a potential strategy to suppress tumor growth.

Genetic control of rhizosphere microbiome of the cotton plants under field conditions.

Understanding the extent of heritability of a plant-associated microbiome (phytobiome) is critically important for exploitation of phytobiomes in agriculture. Two crosses were made between pairs of cotton cultivars (Z2 and J11, L1 and Z49) with differential resistance to Verticillium wilt. F2 plants were grown in a field, together with the four parents to study the heritability of cotton rhizosphere microbiome. Amplicon sequencing was used to profile bacterial and fungal communities in the rhizosphere. F2 offspring plants of both crosses had higher average alpha diversity indices than the two parents; parents differed significantly from F2 offspring in Bray-Curtis beta diversity indices as well. Two types of data were used to study the heritability of rhizosphere microbiome: principal components (PCs) and individual top microbial operational taxonomic units (OTUs). For the L1 × Z49 cross, the variance among the F2 progeny genotypes (namely, genetic variance, VT) was significantly greater than the random variability (VE) for 12 and 34 out of top 100 fungal and bacterial PCs, respectively. For the Z2 × J11 cross, the corresponding values were 10 and 20 PCs. For 29 fungal OTUs and 10 bacterial OTUs out of the most abundant 100 OTUs, genetic variance (VT) was significantly greater than VE for the L1 × Z49 cross; the corresponding values for the Z2 × J11 cross were 24 and one. The estimated heritability was mostly in the range of 40% to 60%. These results suggested the existence of genetic control of polygenic nature for specific components of rhizosphere microbiome in cotton. KEY POINTS: • F2 offspring cotton plants differed significantly from parents in rhizosphere microbial diversity. • Specific rhizosphere components are likely to be genetically controlled by plants. • Common PCs and specific microbial groups are significant genetic components between the two crosses.

Cellular redox sensor HSCARG negatively regulates the translesion synthesis pathway and exacerbates mammary tumorigenesis.

The translesion synthesis (TLS) pathway is a double-edged sword in terms of genome integrity. Deficiency in TLS leads to generation of DNA double strand break (DSB) during replication stress, while excessive activation of the TLS pathway increases the risk of point mutation. Here we demonstrate that HSCARG, a cellular redox sensor, directly interacts with the key protein PCNA in the TLS pathway. HSCARG enhances the interaction between PCNA and the deubiquitinase complex USP1/UAF1 and inhibits the monoubiquitination of PCNA, thereby impairing the recruitment of Y-family polymerases and increasing cell sensitivity to stimuli that trigger replication fork blockades. In response to oxidative stress, disaggregation of HSCARG dimers into monomers and the nuclear transport of HSCARG activate the regulatory function of HSCARG in the TLS pathway. Moreover, HSCARG, which is highly expressed in breast carcinoma, promotes the accumulation of DSBs and mutations. HSCARG knockout PyMT transgenic mice exhibit delayed mammary tumorigenesis compared with that in HSCARG wild-type or heterozygous PyMT mice. Taken together, these findings expand our understanding of TLS regulatory mechanisms and establish a link between the cellular redox status and the DNA damage response (DDR).

Maternal exposure to tributyltin during early gestation increases adverse pregnancy outcomes by impairing placental development.

Tributyltin (TBT) is a persistent organotin pollutant widely used as agricultural and wood biocides, exhibiting well-documented toxicity to reproductive functions in aquatic organisms. However, the effect of TBT on early pregnancy and placental development has been rarely studied in mice. Pregnant mice were fed with 0, 0.2, and 2 mg/kg/day TBT from gravid day 1 to day 8 or 13. TBT exposure led to an increase in the number of resorbed embryo and a reduction in the weight of fetus at gestational days 13. Further study showed that TBT significantly decreased placental weight and area, lowered laminin immunoreactivity and the expressions of placental development-related molecules including Fra1, Eomes, Hand1, and Ascl2. Moreover, TBT treatment markedly inhibited the placental proliferation and induced up-regulation of p53 and cleaved caspase-3 proteins, and down-regulation of Bcl-2 protein. In addition, TBT administration increased levels of malondialdehyde and H2 O2 and decreased activities of catalase and superoxide dismutase. Collectively, these results suggested TBT-induced adverse pregnancy outcomes during early pregnancy might be involved in developmental disorders of the placenta via dysregulation of key molecules, proliferation, apoptosis, and oxidative stress.

Ribosomal protein L6 (RPL6) is recruited to DNA damage sites in a poly(ADP-ribose) polymerase-dependent manner and regulates the DNA damage response.

Ribosomal proteins are the building blocks of ribosome biogenesis. Beyond their known participation in ribosome assembly, the ribosome-independent functions of ribosomal proteins are largely unknown. Here, using immunoprecipitation, subcellular fractionation, His-ubiquitin pulldown, and immunofluorescence microscopy assays, along with siRNA-based knockdown approaches, we demonstrate that ribosomal protein L6 (RPL6) directly interacts with histone H2A and is involved in the DNA damage response (DDR). We found that in response to DNA damage, RPL6 is recruited to DNA damage sites in a poly(ADP-ribose) polymerase (PARP)-dependent manner, promoting its interaction with H2A. We also observed that RPL6 depletion attenuates the interaction between mediator of DNA damage checkpoint 1 (MDC1) and H2A histone family member X, phosphorylated (γH2AX), impairs the accumulation of MDC1 at DNA damage sites, and reduces both the recruitment of ring finger protein 168 (RNF168) and H2A Lys-15 ubiquitination (H2AK15ub). These RPL6 depletion-induced events subsequently inhibited the recruitment of the following downstream repair proteins: tumor protein P53-binding protein 1 (TP53BP1) and BRCA1, DNA repair-associated (BRCA1). Moreover, the RPL6 knockdown resulted in defects in the DNA damage-induced G2-M checkpoint, DNA damage repair, and cell survival. In conclusion, our study identifies RPL6 as a critical regulatory factor involved in the DDR. These findings expand our knowledge of the extraribosomal functions of ribosomal proteins in cell physiology and deepen our understanding of the molecular mechanisms underlying DDR regulation.

Gestational exposure to bisphenol AF causes endocrine disorder of corpus luteum by altering ovarian SIRT-1/Nrf2/NF-kB expressions and macrophage proangiogenic function in mice.

Bisphenol AF (BPAF) is extensively used in industrial production as an emerging substitute for the earlier-used bisphenol A (BPA). Studies have found that BPAF had stronger estrogenic activities than BPA. However, the effects of BPAF on the luteal function of pregnancy and its possible mechanisms are largely unknown. In this study, pregnant mice were orally administered 3.0 and 30 mg/kg/day of BPAF from gestational day (GD) 1 to 8, and samples were collected on GD 8 and GD 19. Results showed that maternal exposure to BPAF impaired embryo implantation and reduced ovarian weight, and interfered with steroid hormone secretion, and decreased the numbers and areas of corpus luteum. BPAF treatment significantly down-regulated expression levels of ovarian Star, Cyp11a, Hsd3b1, and Cyp19a1 mRNA and CYP19a1 and ERα proteins. BPAF also disrupted markers of redox/inflammation key, including silent information regulator of transcript-1 (SIRT-1), nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor kappa-B (NF-ĸB) expressions along with reduced ovarian antioxidant (CAT and SOD) capacity, enhanced oxidant (H2O2 and MDA) and inflammatory factor (Il6 and Tnfa) activities. Furthermore, BPAF exposure inhibited macrophages with a pro-angiogenic phenotype that specifically expressed TIE-2, accompanied by inhibition of angiogenic factors (HIF1a, VEGFA, and Angpt1) and promotion of anti-angiogenic factor Ang-2 to suppress luteal angiogenesis. In addition, BPAF administration also induced luteolysis and apoptosis by up-regulation of COX-2, BAX/BCL-2, and Cleaved-Caspase-3 protein. Collectively, our current data demonstrated that gestational exposure to BPAF caused luteal endocrine disorder by altering ovarian SIRT-1/Nrf2/NF-kB expressions and macrophage proangiogenic function in mice.

Effects of coastal saline-alkali soil on rhizosphere microbial community and crop yield of cotton at different growth stages.

Soil salinization is a global constraint that significantly hampers agricultural production, with cotton being an important cash crop that is not immune to its detrimental effects. The rhizosphere microbiome plays a critical role in plant health and growth, which assists plants in resisting adverse abiotic stresses including soil salinization. This study explores the impact of soil salinization on cotton, including its effects on growth, yield, soil physical and chemical properties, as well as soil bacterial community structures. The results of ß-diversity analysis showed that there were significant differences in bacterial communities in saline-alkali soil at different growth stages of cotton. Besides, the more severity of soil salinization, the more abundance of Proteobacteria, Bacteroidota enriched in rhizosphere bacterial composition where the abundance of Acidobacteriota exhibited the opposite trend. And the co-occurrence network analysis showed that soil salinization affected the complexity of soil bacterial co-occurrence network. These findings provide valuable insights into the mechanisms by which soil salinization affects soil microorganisms in cotton rhizosphere soil and offer guidance for improving soil salinization using beneficial microorganisms.

Maternal exposure to a glyphosate-based herbicide impairs placental development through endoplasmic reticulum stress in mice.

Glyphosate-based herbicides (GBHs) are the most widely used agrochemicals worldwide, increasing the risk of their occurrence in the environment. This study aimed to explore effects and mechanisms of GBH exposure on placental development in vivo during pregnancy in mice. Pregnant mice received GBH by gavage at 0, 5, and 50 mg⋅kg-1⋅day-1 doses from gestational day (GD) 1 to GD 13 and were sacrificed on GD 13 or GD19. Our data indicated that GBH administration significantly increased the number of resorbed fetuses, reduced the weight of fetuses and placentas, and inhibited placental growth, as evident from decreased placental total area and spongiotrophoblast area on GD 19. GBH treatment also inhibited proliferation and induced apoptosis of placenta via upregulation of Bax, cleaved caspase-3 and -12 expression, and downregulation of B cell lymphoma (Bcl)-2 expression. Further study showed that GBH exposure significantly increased expression levels of glucose-regulated protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and C/EBP homologous protein (CHOP) mRNAs and proteins and triggered oxidative stress in placenta on GD 13 and GD 19. In conclusion, our findings suggest that maternal exposure to GBH can impair placental development through the endoplasmic reticulum stress-mediated activation of GRP78/PERK/CHOP signaling pathway in mice.

Soil bacterial community response to continuous cropping of cotton.

Introduction: Long-term continuous cropping may result in the outbreak and proliferation of soil-borne diseases, as well as reduction in annual crop production. Overcoming the obstacles of continuous cropping is critical for the long-term growth of modern agriculture. Soil microbes are essential for plant health, but the consequences of continuous cropping on soil microbiome are still poorly understood. Methods: This study analyzed changes in soil bacterial community composition of Aksu (AKS) and Shihezi (SHZ) in Xinjiang Province during 1-20 years of continuous cropping by 16S amplicon sequencing. The results showed that the incidence of cotton Verticillium wilt rose with the number of cropping years. The bacterial alpha diversity in the AKS soil grew as the number of continuous cropping years increased, however it declined in the SHZ soil. Results: The results of beta diversity analysis showed that there were significant differences in soil bacterial communities between different continuous cropping years and between different soils. The results of community composition changes at the level of main phyla and genus showed that the relative abundance of Actinobacteria, Bacteroidetes and Streptomyces decreased with the increase of continuous cropping years in the AKS and the SHZ soils. In addition, Actinobacteria, Propionibacteriales, and Nocardioidaceae were significantly enriched during the early stages of continuous cropping. Network analysis showed that long-term (≥8 years) continuous cropping interfered with the complexity of soil bacterial co-occurrence networks and reduced collaboration between OTUs. Discussion: These findings suggested that continuous cropping and soil origin jointly affected the diversity and structural of bacterial communities, and the loss of Nocardioidaceae and Streptomyces in Actinobacteria might be one of the reasons of continuous cropping obstacles.

Repurposing a tricyclic antidepressant in tumor and metabolism disease treatment through fatty acid uptake inhibition.

Fatty acid uptake is essential for cell physiological function, but detailed mechanisms remain unclear. Here, we generated an acetyl-CoA carboxylases (ACC1/2) double-knockout cell line, which lacked fatty acid biosynthesis and survived on serum fatty acids and was used to screen for fatty acid uptake inhibitors. We identified a Food and Drug Administration-approved tricyclic antidepressant, nortriptyline, that potently blocked fatty acid uptake both in vitro and in vivo. We also characterized underlying mechanisms whereby nortriptyline provoked lysosomes to release protons and induce cell acidification to suppress macropinocytosis, which accounted for fatty acid endocytosis. Furthermore, nortriptyline alone or in combination with ND-646, a selective ACC1/2 inhibitor, significantly repressed tumor growth, lipogenesis, and hepatic steatosis in mice. Therefore, we show that cells actively take up fatty acids through macropinocytosis, and we provide a potential strategy suppressing tumor growth, lipogenesis, and hepatic steatosis through controlling the cellular level of fatty acids.

Integrated microbiology and metabolomics analysis reveal responses of cotton rhizosphere microbiome and metabolite spectrum to conventional seed coating agents.

Fludioxonil (FL) and metalaxyl-M·fludioxonil·azoxystrobin (MFA) are conventional seed coating agents for controlling cotton seedling diseases. However, their effects on seed endophytic and rhizosphere microecology are still poorly understood. This study aimed to assess the effects of FL and MFA on cotton seed endophytes, rhizosphere soil enzymatic activities, microbiome and metabolites. Both seed coating agents significantly changed seed endophytic bacterial and fungal communities. Growing coated seeds in the soils originating from the Alar (AL) and Shihezi (SH) region inhibited soil catalase activity and decreased both bacterial and fungal biomass. Seed coating agents increased rhizosphere bacterial alpha diversity for the first 21 days but decreased fungal alpha diversity after day 21 in the AL soil. Seed coating reduced the abundance of a number of beneficial microorganisms but enriched some potential pollutant-degrading microorganisms. Seed coating agents may have affected the complexity of the co-occurrence network of the microbiome in the AL soil, reducing connectivity, opposite to what was observed in the SH soil. MFA had more pronounced effects on soil metabolic activities than FL. Furthermore, there were strong links between soil microbial communities, metabolites and enzymatic activities. These findings provide valuable information for future research and development on application of seed coatings for disease management.

De novo pyrimidine biosynthetic complexes support cancer cell proliferation and ferroptosis defence.

De novo pyrimidine biosynthesis is achieved by cytosolic carbamoyl-phosphate synthetase II, aspartate transcarbamylase and dihydroorotase (CAD) and uridine 5'-monophosphate synthase (UMPS), and mitochondrial dihydroorotate dehydrogenase (DHODH). However, how these enzymes are orchestrated remains enigmatical. Here we show that cytosolic glutamate oxaloacetate transaminase 1 clusters with CAD and UMPS, and this complex then connects with DHODH, which is mediated by the mitochondrial outer membrane protein voltage-dependent anion-selective channel protein 3. Therefore, these proteins form a multi-enzyme complex, named 'pyrimidinosome', involving AMP-activated protein kinase (AMPK) as a regulator. Activated AMPK dissociates from the complex to enhance pyrimidinosome assembly but inactivated UMPS, which promotes DHODH-mediated ferroptosis defence. Meanwhile, cancer cells with lower expression of AMPK are more reliant on pyrimidinosome-mediated UMP biosynthesis and more vulnerable to its inhibition. Our findings reveal the role of pyrimidinosome in regulating pyrimidine flux and ferroptosis, and suggest a pharmaceutical strategy of targeting pyrimidinosome in cancer treatment.

Identification of purine biosynthesis as an NADH-sensing pathway to mediate energy stress.

An enhanced NADH/NAD+ ratio, termed reductive stress, is associated with many diseases. However, whether a downstream sensing pathway exists to mediate pathogenic outcomes remains unclear. Here, we generate a soluble pyridine nucleotide transhydrogenase from Escherichia coli (EcSTH), which can elevate the NADH/NAD+ ratio and meantime reduce the NADPH/NADP+ ratio. Additionally, we fuse EcSTH with previously described LbNOX (a water-forming NADH oxidase from Lactobacillus brevis) to resume the NADH/NAD+ ratio. With these tools and by using genome-wide CRISPR/Cas9 library screens and metabolic profiling in mammalian cells, we find that accumulated NADH deregulates PRPS2 (Ribose-phosphate pyrophosphokinase 2)-mediated downstream purine biosynthesis to provoke massive energy consumption, and therefore, the induction of energy stress. Blocking purine biosynthesis prevents NADH accumulation-associated cell death in vitro and tissue injury in vivo. These results underscore the pathophysiological role of deregulated purine biosynthesis in NADH accumulation-associated disorders and demonstrate the utility of EcSTH in manipulating NADH/NAD+ and NADPH/NADP+.

Influence of plant genotype and soil on the cotton rhizosphere microbiome.

Rhizosphere microbial communities are recognized as crucial products of intimate interactions between plant and soil, playing important roles in plant growth and health. Enhancing the understanding of this process is a promising way to promote the next green revolution by applying the multifunctional benefits coming with rhizosphere microbiomes. In this study, we propagated eight cotton genotypes (four upland cotton cultivars and four sea-land cotton cultivars) with varying levels of resistance to Verticillium dahliae in three distinct soil types. Amplicon sequencing was applied to profile both bacterial and fungal communities in the rhizosphere of cotton. The results revealed that soil origin was the primary factor causing divergence in rhizosphere microbial community, with plant genotype playing a secondary role. The Shannon and Simpson indices revealed no significant differences in the rhizosphere microbial communities of Gossypium barbadense and G. hirsutum. Soil origin accounted for 34.0 and 59.05% of the total variability in the PCA of the rhizosphere bacterial and fungal communities, respectively, while plant genotypes within species only accounted for 1.1 to 6.6% of the total variability among microbial population. Similar results were observed in the Bray-Curtis indices. Interestingly, the relative abundance of Acidobacteria phylum in G. barbadense was greater in comparison with that of G. hirsutum. These findings suggested that soil origin and cotton genotype modulated microbiome assembly with soil predominantly shaping rhizosphere microbiome assembly, while host genotype slightly tuned this recruitment process by changing the abundance of specific microbial consortia.

Compound 968 reverses adriamycin resistance in breast cancer MCF-7ADR cells via inhibiting P-glycoprotein function independently of glutaminase.

Adriamycin (ADR) is a chemotherapeutic drug widely utilized to treat multiple types of cancers; however, the clinical efficacy of ADR is compromised due to the development of drug resistance in patients. The combination of drugs with ADR may provide a better therapeutic regimen to overcome this obstacle. Glutaminase (GLS) has been explored as a therapeutic cancer target, and its inhibition also results in increased sensitivity of tumor cells to chemotherapeutic agents. This study aimed to investigate whether GLS inhibition could reverse ADR resistance. We treated the ADR-resistant MCF-7 (MCF-7ADR) cells with a GLS inhibitor, compound 968 or CB-839, in combination with ADR. We found that compound 968, rather than CB-839, together with ADR synergistically inhibited the cell viability. These results indicated that compound 968 reversed ADR resistance in MCF-7ADR cells independently of GLS. Moreover, we modified the structure of compound 968 and finally obtained a compound 968 derivative, SY-1320, which was more potent than compound 968 in eliminating the drug resistance in MCF-7ADR cells. Furthermore, using drug affinity responsive target stability and streptavidin-biotin immunoprecipitation assays, we demonstrated that SY-1320 could specifically target P-glycoprotein (P-gp) and increase ADR accumulation through inhibition of P-gp, thereby resulting in cell death in MCF-7ADR cells. Together, our findings indicate that compound 968 or SY-1320 might be a promising drug for new combination chemotherapy in breast cancer to overcome the drug resistance.

SY-1530, a highly selective BTK inhibitor, effectively treats B-cell malignancies by blocking B-cell activation.

OBJECTIVE: B-cell antigen receptor (BCR) signaling is required to maintain the physiological functions of normal B cells and plays an important pathogenic role in B-cell malignancies. Bruton tyrosine kinase (BTK), a critical mediator of BCR signaling, is an attractive target for the treatment of B-cell malignancies. This study aimed to identify a highly potent and selective BTK inhibitor. METHODS: Homogeneous time-resolved fluorescence assays were used to screen BTK inhibitors. Typhoon fluorescence imaging and Western blot analysis were used to confirm the effects of SY-1530 on the BCR signaling pathway. Additionally, the anti-tumor activities of SY-1530 were evaluated in TMD8 xenografts and spontaneous canine B-cell lymphoma. RESULTS: We found a novel irreversible and non-competitive inhibitor of BTK, SY-1530, which provided dose-dependent and time-dependent inhibition. SY-1530 selectively bound to BTK rather than inducible T-cell kinase; consequently, it did not significantly affect T-cell receptor signaling and caused limited off-target effects. SY-1530 blocked the BCR signaling pathway through down-regulation of BTK activity, thus leading to impaired phosphorylation of BTK and its downstream kinases. Moreover, SY-1530 induced apoptosis in a caspase-dependent manner and efficaciously inhibited tumor growth in mouse xenograft models of B-cell malignancy (P < 0.001). SY-1530 also induced positive clinical responses in spontaneous canine B-cell lymphoma. CONCLUSIONS: SY-1530 is an irreversible and selective BTK inhibitor that shows inhibitory effects on B-cell malignancies by blocking the BCR signaling pathway. Therefore, it may be a promising therapeutic approach for the treatment of B-cell malignancies.

Amminelithium amidoborane Li(NH3)NH2BH3: a new coordination compound with favorable dehydrogenation characteristics.

The monoammoniate of lithium amidoborane, Li(NH(3))NH(2)BH(3), was synthesized by treatment of LiNH(2)BH(3) with ammonia at room temperature. This compound exists in the amorphous state at room temperature, but at -20 degrees C crystallizes in the orthorhombic space group Pbca with lattice parameters of a = 9.711(4), b = 8.7027(5), c = 7.1999(1) A, and V = 608.51 A(3). The thermal decomposition behavior of this compound under argon and under ammonia was investigated. Through a series of experiments we have demonstrated that Li(NH(3))NH(2)BH(3) is able to absorb/desorb ammonia reversibly at room temperature. In the temperature range of 40-70 degrees C, this compound showed favorable dehydrogenation characteristics. Specifically, under ammonia this material was able to release 3.0 equiv hydrogen (11.18 wt %) rapidly at 60 degrees C, which represents a significant advantage over LiNH(2)BH(3). It has been found that the formation of the coordination bond between ammonia and Li(+) in LiNH(2)BH(3) plays a crucial role in promoting the combination of hydridic B-H bonds and protic N-H bonds, leading to dehydrogenation at low temperature.

Inhibiting both proline biosynthesis and lipogenesis synergistically suppresses tumor growth.

Cancer cells often proliferate under hypoxia and reprogram their metabolism. However, how to find targets to effectively block the hypoxia-associated metabolic pathways remains unclear. Here, we developed a tool to conveniently calculate electrons dissipated in metabolic transformations. Based on the law of conservation of electrons in chemical reactions, we further built up an electron balance model for central carbon metabolism, and it can accurately outline metabolic plasticity under hypoxia. Our model specifies that glutamine metabolism reprogrammed for biosynthesis of lipid and/or proline actually acts as the alternative electron bin to enable electron transfer in proliferating cells under hypoxia. Inhibition of both proline biosynthesis and lipogenesis can synergistically suppress cancer cell growth under hypoxia and in vivo tumor onset. Therefore, our model helps to reveal combinations of potential targets to inhibit tumor growth by blocking hypoxia-rewired metabolism and provides a useful tool for future studies on cancer metabolism.

The Deubiquitinase USP38 Promotes NHEJ Repair through Regulation of HDAC1 Activity and Regulates Cancer Cell Response to Genotoxic Insults.

The DNA damage response (DDR) is essential for maintaining genome integrity. Mounting evidence reveals that protein modifications play vital roles in the DDR. Here, we show that USP38 is involved in the DDR by regulating the activity of HDAC1. In response to DNA damage, USP38 interacted with HDAC1 and specifically removed the K63-linked ubiquitin chain promoting the deacetylase activity of HDAC1. As a result, HDAC1 was able to deacetylate H3K56. USP38 deletion resulted in persistent focal accumulation of nonhomologous end joining (NHEJ) factors at DNA damage sites and impaired NHEJ efficiency, causing genome instability and sensitizing cancer cells to genotoxic insults. Knockout of USP38 rendered mice hypersensitive to irradiation and shortened survival. In addition, USP38 was expressed at low levels in certain types of cancers including renal cell carcinoma, indicating dysregulation of USP38 expression contributes to genomic instability and may lead to tumorigenesis. In summary, this study identifies a critical role of USP38 in modulating genome integrity and cancer cell resistance to genotoxic insults by deubiquitinating HDAC1 and regulating its deacetylation activity. SIGNIFICANCE: This study demonstrates that USP38 regulates genome stability and mediates cancer cell resistance to DNA-damaging therapy, providing insight into tumorigenesis and implicating USP38 as a potential target for cancer diagnosis.