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1.
Mol Cell ; 83(24): 4570-4585.e7, 2023 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-38092000

RESUMEN

The nucleotide-binding domain (NBD), leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is a critical mediator of the innate immune response. How NLRP3 responds to stimuli and initiates the assembly of the NLRP3 inflammasome is not fully understood. Here, we found that a cellular metabolite, palmitate, facilitates NLRP3 activation by enhancing its S-palmitoylation, in synergy with lipopolysaccharide stimulation. NLRP3 is post-translationally palmitoylated by zinc-finger and aspartate-histidine-histidine-cysteine 5 (ZDHHC5) at the LRR domain, which promotes NLRP3 inflammasome assembly and activation. Silencing ZDHHC5 blocks NLRP3 oligomerization, NLRP3-NEK7 interaction, and formation of large intracellular ASC aggregates, leading to abrogation of caspase-1 activation, IL-1ß/18 release, and GSDMD cleavage, both in human cells and in mice. ABHD17A depalmitoylates NLRP3, and one human-heritable disease-associated mutation in NLRP3 was found to be associated with defective ABHD17A binding and hyper-palmitoylation. Furthermore, Zdhhc5-/- mice showed defective NLRP3 inflammasome activation in vivo. Taken together, our data reveal an endogenous mechanism of inflammasome assembly and activation and suggest NLRP3 palmitoylation as a potential target for the treatment of NLRP3 inflammasome-driven diseases.


Asunto(s)
Aciltransferasas , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Humanos , Ratones , Caspasa 1/metabolismo , Histidina/metabolismo , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Lipoilación , Macrófagos/metabolismo , Quinasas Relacionadas con NIMA/genética , Quinasas Relacionadas con NIMA/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Aciltransferasas/genética , Aciltransferasas/metabolismo
2.
Mol Cell ; 81(9): 1890-1904.e7, 2021 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-33657401

RESUMEN

O-linked ß-N-acetyl glucosamine (O-GlcNAc) is attached to proteins under glucose-replete conditions; this posttranslational modification results in molecular and physiological changes that affect cell fate. Here we show that posttranslational modification of serine/arginine-rich protein kinase 2 (SRPK2) by O-GlcNAc regulates de novo lipogenesis by regulating pre-mRNA splicing. We found that O-GlcNAc transferase O-GlcNAcylated SRPK2 at a nuclear localization signal (NLS), which triggers binding of SRPK2 to importin α. Consequently, O-GlcNAcylated SRPK2 was imported into the nucleus, where it phosphorylated serine/arginine-rich proteins and promoted splicing of lipogenic pre-mRNAs. We determined that protein nuclear import by O-GlcNAcylation-dependent binding of cargo protein to importin α might be a general mechanism in cells. This work reveals a role of O-GlcNAc in posttranscriptional regulation of de novo lipogenesis, and our findings indicate that importin α is a "reader" of an O-GlcNAcylated NLS.


Asunto(s)
Neoplasias de la Mama/metabolismo , Glucosa/metabolismo , Lipogénesis , Procesamiento Proteico-Postraduccional , Proteínas Serina-Treonina Quinasas/metabolismo , Transporte Activo de Núcleo Celular , Animales , Neoplasias de la Mama/genética , Proliferación Celular , Femenino , Glicosilación , Células HEK293 , Humanos , Células MCF-7 , Ratones Desnudos , N-Acetilglucosaminiltransferasas/genética , N-Acetilglucosaminiltransferasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Precursores del ARN/genética , Precursores del ARN/metabolismo , Empalme del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Carga Tumoral , alfa Carioferinas/genética , alfa Carioferinas/metabolismo , beta Carioferinas/genética , beta Carioferinas/metabolismo
3.
Mol Cell ; 74(6): 1215-1226.e4, 2019 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-31053471

RESUMEN

Programmed death ligand 1 (PD-L1, also called B7-H1) is an immune checkpoint protein that inhibits immune function through its binding of the programmed cell death protein 1 (PD-1) receptor. Clinically approved antibodies block extracellular PD-1 and PD-L1 binding, yet the role of intracellular PD-L1 in cancer remains poorly understood. Here, we discovered that intracellular PD-L1 acts as an RNA binding protein that regulates the mRNA stability of NBS1, BRCA1, and other DNA damage-related genes. Through competition with the RNA exosome, intracellular PD-L1 protects targeted RNAs from degradation, thereby increasing cellular resistance to DNA damage. RNA immunoprecipitation and RNA-seq experiments demonstrated that PD-L1 regulates RNA stability genome-wide. Furthermore, we developed a PD-L1 antibody, H1A, which abrogates the interaction of PD-L1 with CMTM6, thereby promoting PD-L1 degradation. Intracellular PD-L1 may be a potential therapeutic target to enhance the efficacy of radiotherapy and chemotherapy in cancer through the inhibition of DNA damage response and repair.


Asunto(s)
Antígeno B7-H1/genética , Reparación del ADN , ADN de Neoplasias/genética , Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Regulación Neoplásica de la Expresión Génica , Receptor de Muerte Celular Programada 1/genética , Animales , Antineoplásicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Cisplatino/farmacología , Daño del ADN , ADN de Neoplasias/metabolismo , Complejo Multienzimático de Ribonucleasas del Exosoma/metabolismo , Rayos gamma/uso terapéutico , Células HCT116 , Células HeLa , Humanos , Proteínas con Dominio MARVEL , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Proteínas de la Mielina , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Proteolisis/efectos de los fármacos , Proteolisis/efectos de la radiación , Estabilidad del ARN/efectos de los fármacos , Estabilidad del ARN/efectos de la radiación , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Nat Chem Biol ; 20(1): 19-29, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37308732

RESUMEN

O-linked ß-N-acetyl glucosamine (O-GlcNAc) is at the crossroads of cellular metabolism, including glucose and glutamine; its dysregulation leads to molecular and pathological alterations that cause diseases. Here we report that O-GlcNAc directly regulates de novo nucleotide synthesis and nicotinamide adenine dinucleotide (NAD) production upon abnormal metabolic states. Phosphoribosyl pyrophosphate synthetase 1 (PRPS1), the key enzyme of the de novo nucleotide synthesis pathway, is O-GlcNAcylated by O-GlcNAc transferase (OGT), which triggers PRPS1 hexamer formation and relieves nucleotide product-mediated feedback inhibition, thereby boosting PRPS1 activity. PRPS1 O-GlcNAcylation blocked AMPK binding and inhibited AMPK-mediated PRPS1 phosphorylation. OGT still regulates PRPS1 activity in AMPK-deficient cells. Elevated PRPS1 O-GlcNAcylation promotes tumorigenesis and confers resistance to chemoradiotherapy in lung cancer. Furthermore, Arts-syndrome-associated PRPS1 R196W mutant exhibits decreased PRPS1 O-GlcNAcylation and activity. Together, our findings establish a direct connection among O-GlcNAc signals, de novo nucleotide synthesis and human diseases, including cancer and Arts syndrome.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Procesamiento Proteico-Postraduccional , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Fosforilación , Glucosa , Nucleótidos/metabolismo , N-Acetilglucosaminiltransferasas/genética , N-Acetilglucosaminiltransferasas/metabolismo
5.
Proc Natl Acad Sci U S A ; 120(20): e2303479120, 2023 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-37155876

RESUMEN

The human tumor suppressor Ring finger protein 20 (RNF20)-mediated histone H2B monoubiquitination (H2Bub) is essential for proper chromosome segregation and DNA repair. However, what is the precise function and mechanism of RNF20-H2Bub in chromosome segregation and how this pathway is activated to preserve genome stability remain unknown. Here, we show that the single-strand DNA-binding factor Replication protein A (RPA) interacts with RNF20 mainly in the S and G2/M phases and recruits RNF20 to mitotic centromeres in a centromeric R-loop-dependent manner. In parallel, RPA recruits RNF20 to chromosomal breaks upon DNA damage. Disruption of the RPA-RNF20 interaction or depletion of RNF20 increases mitotic lagging chromosomes and chromosome bridges and impairs BRCA1 and RAD51 loading and homologous recombination repair, leading to elevated chromosome breaks, genome instability, and sensitivities to DNA-damaging agents. Mechanistically, the RPA-RNF20 pathway promotes local H2Bub, H3K4 dimethylation, and subsequent SNF2H recruitment, ensuring proper Aurora B kinase activation at centromeres and efficient loading of repair proteins at DNA breaks. Thus, the RPA-RNF20-SNF2H cascade plays a broad role in preserving genome stability by coupling H2Bub to chromosome segregation and DNA repair.


Asunto(s)
Reparación del ADN por Recombinación , Proteína de Replicación A , Humanos , Cromatina , Segregación Cromosómica , Reparación del ADN , Inestabilidad Genómica , Histonas/genética , Histonas/metabolismo , Recombinación Homóloga , Proteína de Replicación A/genética , Proteína de Replicación A/metabolismo
6.
Mol Cell ; 68(3): 591-604.e5, 2017 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-29100056

RESUMEN

The Hippo pathway is crucial in organ size control and tissue homeostasis, with deregulation leading to cancer. An extracellular nutrition signal, such as glucose, regulates the Hippo pathway activation. However, the mechanisms are still not clear. Here, we found that the Hippo pathway is directly regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients. Mechanistically, the core component of Hippo pathway (YAP) is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 109. YAP O-GlcNAcylation disrupts its interaction with upstream kinase LATS1, prevents its phosphorylation, and activates its transcriptional activity. And this activation is not dependent on AMPK. We also identified OGT as a YAP-regulated gene that forms a feedback loop. Finally, we confirmed that glucose-induced YAP O-GlcNAcylation and activation promoted tumorigenesis. Together, our data establish a molecular mechanism and functional significance of the HBP in directly linking extracellular glucose signal to the Hippo-YAP pathway and tumorigenesis.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Transformación Celular Neoplásica/metabolismo , Glucosa/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Neoplasias/enzimología , Fosfoproteínas/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Regulación Neoplásica de la Expresión Génica , Glicosilación , Células HEK293 , Células HeLa , Humanos , Ratones Desnudos , Neoplasias/genética , Neoplasias/patología , Fosfoproteínas/genética , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Serina , Transducción de Señal , Factores de Tiempo , Factores de Transcripción , Transcripción Genética , Activación Transcripcional , Proteínas Señalizadoras YAP
7.
EMBO J ; 39(12): e104133, 2020 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-32347575

RESUMEN

Long non-coding RNAs (lncRNAs) are emerging regulators of genomic stability and human disease. However, the molecular mechanisms by which nuclear lncRNAs directly contribute to DNA damage responses remain largely unknown. Using RNA antisense purification coupled with quantitative mass spectrometry (RAP-qMS), we found that the lncRNA BGL3 binds to PARP1 and BARD1, exhibiting unexpected roles in homologous recombination. Mechanistically, BGL3 is recruited to DNA double-strand breaks (DSBs) by PARP1 at an early time point, which requires its interaction with the DNA-binding domain of PARP1. BGL3 also binds the C-terminal BRCT domain and an internal region (amino acids 127-424) of BARD1, which mediates interaction of the BRCA1/BARD1 complex with its binding partners such as HP1γ and RAD51, resulting in BRCA1/BARD1 retention at DSBs. Cells depleted for BGL3 displayed genomic instability and were sensitive to DNA-damaging reagents. Overall, our findings underscore the biochemical versatility of RNA as a mediator molecule in the DNA damage response pathway, which affects the accumulation of BRCA1/BARD1 at DSBs.


Asunto(s)
Proteína BRCA1/metabolismo , Roturas del ADN de Doble Cadena , Daño del ADN , Complejos Multiproteicos/metabolismo , ARN Largo no Codificante/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteína BRCA1/genética , Células HEK293 , Humanos , Células MCF-7 , Complejos Multiproteicos/genética , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Dominios Proteicos , ARN Largo no Codificante/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/genética
8.
Mol Cell ; 61(4): 614-624, 2016 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-26876938

RESUMEN

The AMP-activated protein kinase (AMPK) is the master regulator of metabolic homeostasis by sensing cellular energy status. When intracellular ATP levels decrease during energy stress, AMPK is initially activated through AMP or ADP binding and phosphorylation of a threonine residue (Thr-172) within the activation loop of its kinase domain. Here we report a key molecular mechanism by which AMPK activation is amplified under energy stress. We found that ubiquitination on AMPKα blocks AMPKα phosphorylation by LKB1. The deubiquitinase USP10 specifically removes ubiquitination on AMPKα to facilitate AMPKα phosphorylation by LKB1. Under energy stress, USP10 activity in turn is enhanced through AMPK-mediated phosphorylation of Ser76 of USP10. Thus, USP10 and AMPK form a key feedforward loop ensuring amplification of AMPK activation in response to fluctuation of cellular energy status. Disruption of this feedforward loop leads to improper AMPK activation and multiple metabolic defects.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Ubiquitina Tiolesterasa/química , Ubiquitina Tiolesterasa/metabolismo , Animales , Metabolismo Energético , Activación Enzimática , Células HCT116 , Células HEK293 , Humanos , Ratones , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Serina/metabolismo , Ubiquitinación
9.
Drug Resist Updat ; 67: 100926, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36682222

RESUMEN

AIMS: Nucleotide de novo synthesis is essential to cell growth and survival, and its dysregulation leads to cancers and drug resistance. However, how this pathway is dysregulated in cancer has not been well clarified. This study aimed to identify the regulatory mechanisms of nucleotide de novo synthesis and drug resistance. METHODS: By combining the ChIP-Seq data from the Cistrome Data Browser, RNA sequencing (RNA-Seq) and a luciferase-based promoter assay, we identified transcription factor FOXK2 as a regulator of nucleotide de novo synthesis. To explore the biological functions and mechanisms of FOXK2 in cancers, we conducted biochemical and cell biology assays in vitro and in vivo. Finally, we assessed the clinical significance of FOXK2 in hepatocellular carcinoma. RESULTS: FOXK2 directly regulates the expression of nucleotide synthetic genes, promoting tumor growth and cancer cell resistance to chemotherapy. FOXK2 is SUMOylated by PIAS4, which elicits FOXK2 nuclear translocation, binding to the promoter regions and transcription of nucleotide synthetic genes. FOXK2 SUMOylation is repressed by DNA damage, and elevated FOXK2 SUMOylation promotes nucleotide de novo synthesis which causes resistance to 5-FU in hepatocellular carcinoma. Clinically, elevated expression of FOXK2 in hepatocellular carcinoma patients was associated with increased nucleotide synthetic gene expression and correlated with poor prognoses for patients. CONCLUSION: Our findings establish FOXK2 as a novel regulator of nucleotide de novo synthesis, with potentially important implications for cancer etiology and drug resistance.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Proliferación Celular , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética
10.
Nucleic Acids Res ; 45(5): 2516-2530, 2017 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-27940552

RESUMEN

To prevent genomic instability, cells respond to DNA lesions by blocking cell cycle progression and initiating DNA repair. Homologous recombination repair of DNA breaks requires CtIP-dependent resection of the DNA ends, which is thought to play a key role in activation of CHK1 kinase to induce the cell cycle checkpoint. But the mechanism is still not fully understood. Here, we establish that And-1, a replisome component, promotes DNA-end resection and DNA repair by homologous recombination. Mechanistically, And-1 interacts with CtIP and regulates CtIP recruitment to DNA damage sites. And-1 localizes to sites of DNA damage dependent on MDC1-RNF8 pathway, and is required for resistance to many DNA-damaging and replication stress-inducing agents. Furthermore, we show that And-1-CtIP axis is critically required for sustained ATR-CHK1 checkpoint signaling and for maintaining both the intra-S- and G2-phase checkpoints. Our findings thus identify And-1 as a novel DNA repair regulator and reveal how the replisome regulates the DNA damage induced checkpoint and genomic stability.


Asunto(s)
Proteínas Portadoras/metabolismo , Daño del ADN , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/metabolismo , Reparación del ADN por Recombinación , Puntos de Control del Ciclo Celular , Línea Celular , Replicación del ADN , ADN de Cadena Simple/metabolismo , Proteínas de Unión al ADN/antagonistas & inhibidores , Endodesoxirribonucleasas , Humanos
11.
Nature ; 470(7332): 124-8, 2011 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-21293379

RESUMEN

p53-binding protein 1 (53BP1) is known to be an important mediator of the DNA damage response, with dimethylation of histone H4 lysine 20 (H4K20me2) critical to the recruitment of 53BP1 to double-strand breaks (DSBs). However, it is not clear how 53BP1 is specifically targeted to the sites of DNA damage, as the overall level of H4K20me2 does not seem to increase following DNA damage. It has been proposed that DNA breaks may cause exposure of methylated H4K20 previously buried within the chromosome; however, experimental evidence for such a model is lacking. Here we found that H4K20 methylation actually increases locally upon the induction of DSBs and that methylation of H4K20 at DSBs is mediated by the histone methyltransferase MMSET (also known as NSD2 or WHSC1) in mammals. Downregulation of MMSET significantly decreases H4K20 methylation at DSBs and the subsequent accumulation of 53BP1. Furthermore, we found that the recruitment of MMSET to DSBs requires the γH2AX-MDC1 pathway; specifically, the interaction between the MDC1 BRCT domain and phosphorylated Ser 102 of MMSET. Thus, we propose that a pathway involving γH2AX-MDC1-MMSET regulates the induction of H4K20 methylation on histones around DSBs, which, in turn, facilitates 53BP1 recruitment.


Asunto(s)
Roturas del ADN de Doble Cadena , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/química , Histonas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lisina/metabolismo , Proteínas Represoras/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/metabolismo , Inmunoprecipitación de Cromatina , Proteínas de Unión al ADN/metabolismo , Células HEK293 , Células HeLa , N-Metiltransferasa de Histona-Lisina/química , Humanos , Metilación , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Fosforilación , Fosfoserina/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transporte de Proteínas , Proteínas Represoras/química , Transactivadores/química , Transactivadores/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53
12.
Nucleic Acids Res ; 43(17): 8325-39, 2015 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-26187992

RESUMEN

REV1 is a eukaryotic member of the Y-family of DNA polymerases involved in translesion DNA synthesis and genome mutagenesis. Recently, REV1 is also found to function in homologous recombination. However, it remains unclear how REV1 is recruited to the sites where homologous recombination is processed. Here, we report that loss of mammalian REV1 results in a specific defect in replication-associated gene conversion. We found that REV1 is targeted to laser-induced DNA damage stripes in a manner dependent on its ubiquitin-binding motifs, on RAD18, and on monoubiquitinated FANCD2 (FANCD2-mUb) that associates with REV1. Expression of a FANCD2-Ub chimeric protein in RAD18-depleted cells enhances REV1 assembly at laser-damaged sites, suggesting that FANCD2-mUb functions downstream of RAD18 to recruit REV1 to DNA breaks. Consistent with this suggestion we found that REV1 and FANCD2 are epistatic with respect to sensitivity to the double-strand break-inducer camptothecin. REV1 enrichment at DNA damage stripes also partially depends on BRCA1 and BRCA2, components of the FANCD2/BRCA supercomplex. Intriguingly, analogous to FANCD2-mUb and BRCA1/BRCA2, REV1 plays an unexpected role in protecting nascent replication tracts from degradation by stabilizing RAD51 filaments. Collectively these data suggest that REV1 plays multiple roles at stalled replication forks in response to replication stress.


Asunto(s)
Daño del ADN , Replicación del ADN , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/fisiología , Proteínas Nucleares/fisiología , Nucleotidiltransferasas/fisiología , Camptotecina/toxicidad , Línea Celular , ADN/metabolismo , Proteínas de Unión al ADN/fisiología , ADN Polimerasa Dirigida por ADN , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/metabolismo , Conversión Génica , Humanos , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Nucleotidiltransferasas/química , Nucleotidiltransferasas/metabolismo , Dominios y Motivos de Interacción de Proteínas , Estrés Fisiológico/genética , Inhibidores de Topoisomerasa I/toxicidad , Ubiquitina-Proteína Ligasas
13.
Nucleic Acids Res ; 42(9): 5594-604, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24692660

RESUMEN

Histone H2B O-GlcNAcylation is an important post-translational modification of chromatin during gene transcription. However, how this epigenetic modification is regulated remains unclear. Here we found that the energy-sensing adenosine-monophosphate-activated protein kinase (AMPK) could suppress histone H2B O-GlcNAcylation. AMPK directly phosphorylates O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase (OGT). Although this phosphorylation does not regulate the enzymatic activity of OGT, it inhibits OGT-chromatin association, histone O-GlcNAcylation and gene transcription. Conversely, OGT also O-GlcNAcylates AMPK and positively regulates AMPK activity, creating a feedback loop. Taken together, these results reveal a crosstalk between the LKB1-AMPK and the hexosamine biosynthesis (HBP)-OGT pathways, which coordinate together for the sensing of nutrient state and regulation of gene transcription.


Asunto(s)
Proteínas Quinasas Activadas por AMP/fisiología , Histonas/metabolismo , Procesamiento Proteico-Postraduccional , Acetilglucosamina/metabolismo , Cromatina/metabolismo , Metabolismo Energético , Epigénesis Genética , Glicosilación , Células Hep G2 , Homeostasis , Humanos , N-Acetilglucosaminiltransferasas/metabolismo , Fosforilación , Transcripción Genética
14.
J Immunol ; 190(2): 756-63, 2013 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-23241889

RESUMEN

Wolf-Hirschhorn syndrome (WHS) is a genetic disease with characteristic facial features and developmental disorders. Of interest, loss of the MMSET gene (also known as WHSC1) is considered to be responsible for the core phenotypes of this disease. Patients with WHS also display Ab deficiency, although the underlying cause of this deficiency is unclear. Recent studies suggest that the histone methyltransferase activity of MMSET plays an important role in the DNA damage response by facilitating the recruitment of 53BP1 to sites of DNA damage. We hypothesize that MMSET also regulates class switch recombination (CSR) through its effect on 53BP1. In this study, we show that MMSET indeed plays an important role in CSR through its histone methyltransferase activity. Knocking down MMSET expression impaired 53BP1 recruitment as well as the germline transcription of the Igh switch regions, resulting in defective CSR but no effect on cell growth and viability. These results suggest that defective CSR caused by MMSET deficiency could be a cause of Ab deficiency in WHS patients.


Asunto(s)
N-Metiltransferasa de Histona-Lisina/metabolismo , Cambio de Clase de Inmunoglobulina/genética , Proteínas Represoras/metabolismo , Recombinación V(D)J/genética , Línea Celular , Regulación de la Expresión Génica , Sitios Genéticos , Histonas/metabolismo , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Metilación , Unión Proteica , Transcripción Genética , Proteína 1 de Unión al Supresor Tumoral P53 , Síndrome de Wolf-Hirschhorn/genética
15.
Chin Med J (Engl) ; 137(7): 818-829, 2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38494343

RESUMEN

ABSTRACT: Lung cancer is one of the most common malignancies and has the highest number of deaths among all cancers. Despite continuous advances in medical strategies, the overall survival of lung cancer patients is still low, probably due to disease progression or drug resistance. Ferroptosis is an iron-dependent form of regulated cell death triggered by the lethal accumulation of lipid peroxides, and its dysregulation is implicated in cancer development. Preclinical evidence has shown that targeting the ferroptosis pathway could be a potential strategy for improving lung cancer treatment outcomes. In this review, we summarize the underlying mechanisms and regulatory networks of ferroptosis in lung cancer and highlight ferroptosis-targeting preclinical attempts to provide new insights for lung cancer treatment.


Asunto(s)
Ferroptosis , Neoplasias Pulmonares , Humanos , Progresión de la Enfermedad , Peróxidos Lipídicos
16.
Cancer Lett ; 587: 216696, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38331089

RESUMEN

Lactate dehydrogenase A (LDHA) serves as a key regulator of the Warburg Effect by catalyzing the conversion of pyruvate to lactate in the final step of glycolysis. Both the expression level and enzyme activity of LDHA are upregulated in cancers, however, the underlying mechanism remains incompletely understood. Here, we show that LDHA is post-translationally palmitoylated by ZDHHC9 at cysteine 163, which promotes its enzyme activity, lactate production, and reduces reactive oxygen species (ROS) generation. Replacement of endogenous LDHA with a palmitoylation-deficient mutant leads to reduced pancreatic cancer cell proliferation, increased T-cell infiltration, and limited tumor growth; it also affects pancreatic cancer cell response to chemotherapy. Moreover, LDHA palmitoylation is upregulated in gemcitabine resistant pancreatic cancer cells. Clinically, ZDHHC9 is upregulated in pancreatic cancer and correlated with poor prognoses for patients. Overall, our findings identify ZDHHC9-mediated palmitoylation as a positive regulator of LDHA, with potentially significant implications for cancer etiology and targeted therapy for pancreatic cancer.


Asunto(s)
L-Lactato Deshidrogenasa , Neoplasias Pancreáticas , Humanos , L-Lactato Deshidrogenasa/genética , Lipoilación , Línea Celular Tumoral , Lactato Deshidrogenasa 5/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Glucólisis , Proliferación Celular , Lactatos
17.
Cancer Lett ; 588: 216742, 2024 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-38401884

RESUMEN

O-linked-N-acetylglucosaminylation (O-GlcNAcylation), a dynamic post-translational modification (PTM), holds profound implications in controlling various cellular processes such as cell signaling, metabolism, and epigenetic regulation that influence cancer progression and therapeutic resistance. From the therapeutic perspective, O-GlcNAc modulates drug efflux, targeting and metabolism. By integrating signals from glucose, lipid, amino acid, and nucleotide metabolic pathways, O-GlcNAc acts as a nutrient sensor and transmits signals to exerts its function on genome stability, epithelial-mesenchymal transition (EMT), cell stemness, cell apoptosis, autophagy, cell cycle. O-GlcNAc also attends to tumor microenvironment (TME) and the immune response. At present, several strategies aiming at targeting O-GlcNAcylation are under mostly preclinical evaluation, where the newly developed O-GlcNAcylation inhibitors markedly enhance therapeutic efficacy. Here we systematically outline the mechanisms through which O-GlcNAcylation influences therapy resistance and deliberate on the prospects and challenges associated with targeting O-GlcNAcylation in future cancer treatments.


Asunto(s)
Neoplasias , Azúcares , Humanos , Resistencia a Antineoplásicos , Epigénesis Genética , Procesamiento Proteico-Postraduccional , Neoplasias/tratamiento farmacológico , N-Acetilglucosaminiltransferasas , Acetilglucosamina/metabolismo , Microambiente Tumoral
18.
Cell Rep ; 43(1): 113610, 2024 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-38165804

RESUMEN

Fanconi anemia (FA) is characterized by congenital abnormalities, bone marrow failure, and cancer susceptibility. The central FA protein complex FANCI/FANCD2 (ID2) is activated by monoubiquitination and recruits DNA repair proteins for interstrand crosslink (ICL) repair and replication fork protection. Defects in the FA pathway lead to R-loop accumulation, which contributes to genomic instability. Here, we report that the splicing factor SRSF1 and FANCD2 interact physically and act together to suppress R-loop formation via mRNA export regulation. We show that SRSF1 stimulates FANCD2 monoubiquitination in an RNA-dependent fashion. In turn, FANCD2 monoubiquitination proves crucial for the assembly of the SRSF1-NXF1 nuclear export complex and mRNA export. Importantly, several SRSF1 cancer-associated mutants fail to interact with FANCD2, leading to inefficient FANCD2 monoubiquitination, decreased mRNA export, and R-loop accumulation. We propose a model wherein SRSF1 and FANCD2 interaction links DNA damage response to the avoidance of pathogenic R-loops via regulation of mRNA export.


Asunto(s)
Anemia de Fanconi , Neoplasias , Humanos , Estructuras R-Loop , Transporte Activo de Núcleo Celular , Anemia de Fanconi/metabolismo , Proteínas del Grupo de Complementación de la Anemia de Fanconi/metabolismo , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genética , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/metabolismo , Ubiquitinación , Reparación del ADN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Daño del ADN , Factores de Empalme Serina-Arginina/genética , Factores de Empalme Serina-Arginina/metabolismo
19.
Genes Dis ; 10(6): 2331-2338, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37554216

RESUMEN

De novo nucleotide biosynthetic pathway is a highly conserved and essential biochemical pathway in almost all organisms. Both purine nucleotides and pyrimidine nucleotides are necessary for cell metabolism and proliferation. Thus, the dysregulation of the de novo nucleotide biosynthetic pathway contributes to the development of many human diseases, such as cancer. It has been shown that many enzymes in this pathway are overactivated in different cancers. In this review, we summarize and update the current knowledge on the de novo nucleotide biosynthetic pathway, regulatory mechanisms, its role in tumorigenesis, and potential targeting opportunities.

20.
Cancer Med ; 12(1): 488-499, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35666017

RESUMEN

BACKGROUND: The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, with deregulation leading to cancer and other diseases. However, how this pathway is dysregulated in cancer has not been well clarified. METHODS: Using a tandem affinity purification/mass-spec technique and biochemical analyses, we identified tumor protein D52 (TPD52) as an AMPKα-interacting molecule. To explore the biological effects of TPD52 in cancers, we conducted biochemical and metabolic assays in vitro and in vivo with cancer cells and TPD52 transgenic mice. Finally, we assessed the clinical significance of TPD52 expression in breast cancer patients using bioinformatics techniques. RESULTS: TPD52, initially identified to be overexpressed in many human cancers, was found to form a stable complex with AMPK in cancer cells. TPD52 directly interacts with AMPKα and inhibits AMPKα kinase activity in vitro and in vivo. In TPD52 transgenic mice, overexpression of TPD52 leads to AMPK inhibition and multiple metabolic defects. Clinically, high TPD52 expression predicts poor survival of breast cancer patients. CONCLUSION: The findings revealed that TPD52 is a novel regulator of energy stress-induced AMPK activation and cell metabolism. These results shed new light on AMPK regulation and understanding of the etiology of cancers with TPD52 overexpression.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Neoplasias de la Mama , Ratones , Animales , Humanos , Femenino , Proteínas Quinasas Activadas por AMP/genética , Proteínas de Neoplasias/metabolismo , Neoplasias de la Mama/patología , Ratones Transgénicos , Línea Celular Tumoral
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