iProXProteomicsJianxiu YuHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX0010103000Jianxiu.Yu@shsmu.edu.cnShanghai Jiaotong University School of MedicineiProXDysregulation of histone supply is implicated in various cancers, including lung adenocarcinoma (LUAD), although the underlying mechanisms remain poorly understood. Here, we demonstrate that knockout of Fbxo45 in mouse alveolar epithelial type 2 (AT2) cells leads to spontaneous LUAD. Our findings reveal that FBXO45 is a novel cell-cycle-regulated protein that is degraded upon phosphorylation by CDK1 during the S/G2 phase. During the S phase or DNA damage repair, FBXO45 binds to UPF1 and recruits the phosphatase PPP6C, thereby inhibiting UPF1 phosphorylation. This process is crucial for preventing the degradation of replication-dependent (RD) histone mRNAs and ensuring an adequate histone supply. In the absence of FBXO45, the impaired interaction between PPP6C and UPF1 results in sustained hyperphosphorylation of UPF1 throughout the cell cycle, leading to an insufficient histone supply, chromatin relaxation, genomic instability, and an increased rate of gene mutations, ultimately culminating in malignant transformation. Notably, analysis of clinical LUAD specimens confirms a positive correlation between the loss of FBXO45 and genomic instability, which is consistent with our findings in the mouse model. These results highlight the critical role of FBXO45 as a genomic guardian in coordinating histone supply and DNA replication, providing valuable insights into potential therapeutic targets and strategies for the treatment of LUAD.Loss of Fbxo45 in AT2 cells leads to insufficient histone supply and initiates lung adenocarcinoma.Li Lian L, Li Junya J, Chen Ran R, Huang Caihu C, Zuo Yong Y, Lu Runhui R, Liu Xiaojia X, Huang Jiayi J, Wang Yanli Y, Zhao Xian X, Cheng Jinke J, Zhao Xiaojing X, Du Chunling C, Yu Jianxiu JMass Spectrum Analysis, Mass Spectrum, B430202H16Rik, MQD22.15, Upf1p, Analyses, Rent1, ATUPF1, DmelCG1559, Proteins, SUP113, HUPF1, upf1, Spectrometry, Gene, Fbx45, MQD22_15, Spectrum Analyses, Spectrum Analysis, DmUpf1, Protein Gene Products, Dm-Upf1, UPF1, Spectroscopy, Gene Proteins, pNORF1, PNORF-1, MS, NORF1, Upflp, Protein, Gene Products, Mass, Mass., MOF4, smg-2, LOW-LEVEL BETA-AMYLASE 1, Analysis, CG1559, RENT1, Mass Spectrum Analyses, Mass Spectroscopy, IFS2bronchogenic lung adenocarcinoma, Lung Adenocarcinomas, Adenocarcinoma, Lung, Spi9, distribution, ATII, supply, adenocarcinoma of lung, LUAD., Fbx45, non-small cell lung adenocarcinoma, ovalbumin, lung type II cell, Histone H1(s), Histone, Adenocarcinomas, Cell, at2, at2r, AT2, nonsmall cell adenocarcinoma, Lung Adenocarcinoma, Histone H2b, Histone H2a, adenocarcinoma of the lung, lung adenocarcinoma, Angiotensin II type-2 receptor, ATGR2, MRX88, Histone H5, Histone H4, Histone H7, TII, supply and distribution, Histone H1, Histone H3.3, Histone H3biochemical pathways, SRM5, MGC130048, Materials, 2.7.11.22, Spi9, determination, Laboratory, Phosphatase, supply, 2.7.11.23, Mus domesticus, fond, A4, Phases, LUAD., protein, Genome Stability, Tumor, CycEI, House Mouse, phosphorylation, Mutations, dmTAF[[II]]230, Cell division control protein 2 homolog, Histone H2b, cdc, Phosphatases, Histone H2a, Hydrolase, Ccne, Roles, Angiotensin II type-2 receptor, Cdc2a, ATGR2, symptoms, l(2)31Eh, Concepts, cellular degradation, Autonomous Replication, pp6, PP6, protein aggregate, Chromatins, IFS2, Dmcdc2, Cell Division Cycles, treatment, gamma sarcoglycan, Gap Phase, Upf1p, TFIID TAF250, cel, S-phase, catabolism, upf1, S, Swiss Mice, Phase 2, Phosphomonoesterases, Autonomous, at2, AT2, cdc2Dm, CG5363, dCdk1, 2310003C10Rik, Cell Cycles, chromosome scaffold, Role Concepts, Cdc2, CDC2, disease management, Histone H5, Therapies, Histone H4, gamma-sarcoglycan, Periods, Histone H7, biotransformation, Malignancies, TII, house mouse, CG1559, phosphatase, Histone H1, Histone H3, Dm cdc2, Tumors, nuclear chromatin, Therapy, screening, dTAF[[II]]230, anatomical protrusion, ATUPF1, ATII, mouse, SG-gamma, TAF200, Fbx45, ovalbumin, TAFII-250, TAF250/230, Cyc E, br37, Adenocarcinomas, DmUpf1, Division Cycles, UPF1, adenocarcinoma of the lung, TAFII250, Benign, Role Concept, BG:DS07108.3, epithelial, DmCdc2, Role, Genetic Materials, sarcoglycan, secretion, Gap, l(2)05206, DmelCG5363, RENT1, Genetic Material, Second Gap Phases, DNA Injury, Mus musculus, DNA Injuries, fast rate, Division Cycle, G2, mice, DmelCG1559, adenocarcinoma of lung, HUPF1, Swiss Mouse, signs, Benign Neoplasms, non-small cell lung adenocarcinoma, INSDC_feature:gene, Second Gap, gamma (35kDa dystrophin-associated glycoprotein), CG17603, TAF[[II]], Treatments, Genomic, Malignant Neoplasms, domesticus, Dm-Upf1, nonsmall cell adenocarcinoma, Lung Adenocarcinoma, Phosphohydrolase, DMDA, l35Dd, Genotoxic, Replications, PP6C, Taf250, p34 protein kinase, spine, Material, 35kD dystrophin-associated glycoprotein, SR3-5, Phosphoric, Cdk-1, Autonomous Replications, Cistron, Mouse, DNA, Hydrolases, Genomic Stabilities, S Periods, TAF230, bronchogenic lung adenocarcinoma, Adenocarcinoma, cytoplasmic chromatin, d230, Lung, MQD22.15, SGCG_HUMAN, cycline, Gap Phase 2, Neoplasms, DmcyclinE, Benign Neoplasm, Gene, dTAFII250, cycE, MQD22_15, Monoester Hydrolase, protein-containing complex, Genomic Stability, Malignant, EfW1, TYPE, l(2)br37, cellular catabolism, CYCLE, Gap Phases, protrusion, DAGA4, cdi7, pNORF1, Stability, cyclinE, House, dmTAF1, Taf230, Instabilities, Upflp, Cycle, 35DAG, Genomic Instabilities, Cdi7, CDI7, Gene Products, Mus musculus domesticus, swo2, smg-2, MAM, gamma-SG, Mice, SCG3, DNA Replications, Genome Instabilities, Histone H3.3, TAF250, Cycles, Taf200, G2 Phases, Injury, dTAF[[II]]250, CYCE, Genetic, Malignancy, CDC28A, Rent1, breakdown of chemical, distribution, Swiss, cell, DmelCG3938, CyclE, LUAD, SUP113, Cell Division Cycle, cell-division cycle, 3938, P34CDC2, Taf1p, Cell Division, DmcycE, S Period, Phosphoric Monoester Hydrolase, Neoplasias, l(2)k05007, dTAF250, dm-cycE, Second Gap Phase, CDK1/CDC2, cdk1, NORF1, hyperphosphorylation, TAF, CDK1, Dcdc2, Cdk1, Cancer, cellular breakdown, B430202H16Rik, TAF[[II]]250, findings, Malignant Neoplasm, 35 kDa dystrophin-associated glycoprotein, degradation, protein complex, Proteins, Phosphorylations, l(3)84Ab, HSL5, BG:DS00004.13, lung type II cell, Cistrons, Histone, Cell, SGCG, LGMD2C, dTAF230, Concept, Stabilities, Phosphomonoesterase, high rate, MT, l(2)k02514, DmCycE, native protein, Period, Mus, p230, Protein, group 4, chemical analysis, Neoplasm, TAF[[II]]250/230, TFIID, supply and distribution, CyeE, LOW-LEVEL BETA-AMYLASE 1, DmCdk1, Replication, Genome Stabilities, epitheliocyte, p34-lt-CDC2-gt-, breakdown of molecule, Lung Adenocarcinomas, Taf[[II]]250, Genotoxic Stress, 5363, Phase, Phosphoric Monoester, TAF[[II]]230, l(2)k02602, DMDA1, biodegradation, l(2)35Dd, S Phases, DNA Lesion, House Mice, phosphoric monoester hydrolase activity, TAF[II]250, Cancers, tws1, Histone H1(s), Cell division protein kinase 1, at2r, Laboratory Mice, Protein Gene Products, p34<CDC2>, Phosphohydrolases, D-CycE, Gene Proteins, DNA Lesions, breakdown of substance, PNORF-1, DmelCG17603, Genome Instability, lung adenocarcinoma, Therapeutic, SCARMD2, Stress, MRX88, Treatment, Second, MOF4, assay, Instability, CG3938, Laboratory Mouse, CDCDm, Neoplasia, Genome, TAF1, Relaxationsbronchogenic lung adenocarcinoma, Lung Adenocarcinomas, Adenocarcinoma, Lung, Spi9, distribution, ATII, supply, adenocarcinoma of lung, LUAD., Fbx45, non-small cell lung adenocarcinoma, ovalbumin, lung type II cell, Histone H1(s), Histone, Adenocarcinomas, Cell, at2, at2r, AT2, nonsmall cell adenocarcinoma, Lung Adenocarcinoma, Histone H2b, Histone H2a, adenocarcinoma of the lung, lung adenocarcinoma, Angiotensin II type-2 receptor, ATGR2, MRX88, Histone H5, Histone H4, Histone H7, TII, supply and distribution, Histone H1, Histone H3.3, Histone H3falseLoss of Fbxo45 in AT2 cells leads to insufficient histone supply and initiates lung adenocarcinomaWe identified proteins that interact with FBXO45 and UPF1 through mass spectrometry.Tue Oct 29 00:00:00 GMT 2024PXD057326960639672818