RESUMEN
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic lipid accumulation, which can progress to nonalcoholic steatohepatitis (NASH). Histone deacetylase Sirtuin 6 (SIRT6) regulates NAFLD by regulating metabolism-related gene expression, but an extrachromosomal role for SIRT6 in NAFLD development remains elusive. We investigated whether SIRT6 functions on NAFLD in the cytoplasm. We found that SIRT6 binds saturated fatty acids, especially palmitic acid. This binding leads to its nuclear export, where it deacetylates long-chain acyl-CoA synthase 5 (ACSL5), thereby facilitating fatty acid oxidation. High-fat diet-induced NAFLD is suppressed by ACSL5 hepatic overexpression but is exacerbated by its depletion. As confirmation, overexpression of a deacetylated ACSL5 mimic attenuated NAFLD in Sirt6 liver-specific knockout mice. Moreover, NASH-hepatic tissues from both patients and diet-fed mice exhibited significantly reduced cytoplasmic SIRT6 levels and increased ACSL5 acetylation. The SIRT6/ACSL5 signaling pathway has a critical role in NAFLD progression and might constitute an avenue for therapeutic intervention.
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Enfermedad del Hígado Graso no Alcohólico , Sirtuinas , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Acilcoenzima A/metabolismo , Ratones Endogámicos C57BL , Hígado/metabolismo , Metabolismo de los Lípidos , Ratones Noqueados , Ácidos Grasos/metabolismo , Sirtuinas/genética , Sirtuinas/metabolismo , Citoplasma/metabolismoRESUMEN
Double-strand breaks (DSBs) are the most lethal form of DNA damage. Transcriptional activity at DSBs, as well as transcriptional repression around DSBs, are both required for efficient DNA repair. The chromatin landscape defines and coordinates these two opposing events. However, how the open and condensed chromatin architecture is regulated remains unclear. Here, we show that the GATAD2B-NuRD complex associates with DSBs in a transcription- and DNA:RNA hybrid-dependent manner, to promote histone deacetylation and chromatin condensation. This activity establishes a spatio-temporal boundary between open and closed chromatin, which is necessary for the correct termination of DNA end resection. The lack of the GATAD2B-NuRD complex leads to chromatin hyperrelaxation and extended DNA end resection, resulting in homologous recombination (HR) repair failure. Our results suggest that the GATAD2B-NuRD complex is a key coordinator of the dynamic interplay between transcription and the chromatin landscape, underscoring its biological significance in the RNA-dependent DNA damage response.
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Cromatina , Roturas del ADN de Doble Cadena , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2 , Cromatina/metabolismo , Cromatina/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , ARN/metabolismo , ARN/genética , Daño del ADN , ADN/metabolismo , ADN/genética , Animales , Humanos , Transcripción Genética , Reparación del ADN , RatonesRESUMEN
MRE11 nuclease forms a trimeric complex (MRN) with RAD50 and NBS1 and plays a central role in preventing genomic instability. When DNA double-strand breaks (DSBs) occur, MRN is quickly recruited to the damage site and initiates DNA end resection; accordingly, MRE11 must be tightly regulated to avoid inefficient repair or nonspecific resection. Here, we show that MRE11 and RAD50 form a complex (MRC) with C1QBP, which stabilizes MRE11/RAD50, while inhibiting MRE11 nuclease activity by preventing its binding to DNA or chromatin. Upon DNA damage, ATM phosphorylates MRE11-S676/S678 to quickly dissociate the MRC complex. Either excess or insufficient C1QBP impedes the recruitment of MRE11 to DSBs and impairs the DNA damage response. C1QBP is highly expressed in breast cancer and positively correlates with MRE11 expression, and the inhibition of C1QBP enhances tumor regression with chemotherapy. By influencing MRE11 at multiple levels, C1QBP is, thus, an important player in the DNA damage response.
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Ácido Anhídrido Hidrolasas/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Recombinación Homóloga , Proteína Homóloga de MRE11/metabolismo , Proteínas Mitocondriales/metabolismo , Complejos Multiproteicos/metabolismo , Proteínas Nucleares/metabolismo , Ácido Anhídrido Hidrolasas/genética , Animales , Proteínas Portadoras/genética , Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Células HEK293 , Células HeLa , Humanos , Proteína Homóloga de MRE11/genética , Proteínas Mitocondriales/genética , Complejos Multiproteicos/genética , Proteínas Nucleares/genética , Estabilidad Proteica , Células Sf9 , SpodopteraRESUMEN
Alternative pre-mRNA-splicing-induced post-transcriptional gene expression regulation is one of the pathways for tumors maintaining proliferation rates accompanying the malignant phenotype under stress. Here, we uncover a list of hyperacetylated proteins in the context of acutely reduced Acetyl-CoA levels under nutrient starvation. PHF5A, a component of U2 snRNPs, can be acetylated at lysine 29 in response to multiple cellular stresses, which is dependent on p300. PHF5A acetylation strengthens the interaction among U2 snRNPs and affects global pre-mRNA splicing pattern and extensive gene expression. PHF5A hyperacetylation-induced alternative splicing stabilizes KDM3A mRNA and promotes its protein expression. Pathologically, PHF5A K29 hyperacetylation and KDM3A upregulation axis are correlated with poor prognosis of colon cancer. Our findings uncover a mechanism of an anti-stress pathway through which acetylation on PHF5A promotes the cancer cells' capacity for stress resistance and consequently contributes to colon carcinogenesis.
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Empalme Alternativo , Carcinogénesis/genética , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Histona Demetilasas con Dominio de Jumonji/genética , Proteínas de Unión al ARN/genética , Transactivadores/genética , Acetilcoenzima A/deficiencia , Acetilación , Animales , Carcinogénesis/metabolismo , Carcinogénesis/patología , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Células HCT116 , Humanos , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Histona Demetilasas con Dominio de Jumonji/metabolismo , Células MCF-7 , Masculino , Ratones , Ratones Desnudos , Pronóstico , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Proteínas de Unión al ARN/antagonistas & inhibidores , Proteínas de Unión al ARN/metabolismo , Ribonucleoproteína Nuclear Pequeña U2/genética , Ribonucleoproteína Nuclear Pequeña U2/metabolismo , Transducción de Señal , Análisis de Supervivencia , Transactivadores/antagonistas & inhibidores , Transactivadores/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Factores de Transcripción p300-CBP/genética , Factores de Transcripción p300-CBP/metabolismoRESUMEN
Breast Cancer Type 1 Susceptibility Protein (BRCA1) is a tumor-suppressor protein that regulates various cellular pathways, including those that are essential for preserving genome stability. One essential mechanism involves a BRCA1-A complex that is recruited to double-strand breaks (DSBs) by RAP80 before initiating DNA damage repair (DDR). How RAP80 itself is recruited to DNA damage sites, however, is unclear. Here, we demonstrate an intrinsic correlation between a methyltransferase DOT1L-mediated RAP80 methylation and BRCA1-A complex chromatin recruitment that occurs during cancer cell radiotherapy resistance. Mechanistically, DOT1L is quickly recruited onto chromatin and methylates RAP80 at multiple lysines in response to DNA damage. Methylated RAP80 is then indispensable for binding to ubiquitinated H2A and subsequently triggering BRCA1-A complex recruitment onto DSBs. Importantly, DOT1L-catalyzed RAP80 methylation and recruitment of BRCA1 have clinical relevance, as inhibition of DOT1L or RAP80 methylation seems to enhance the radiosensitivity of cancer cells both in vivo and in vitro. These data reveal a crucial role for DOT1L in DDR through initiating recruitment of RAP80 and BRCA1 onto chromatin and underscore a therapeutic strategy based on targeting DOT1L to overcome tumor radiotherapy resistance.
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Proteína BRCA1 , Reparación del ADN , Chaperonas de Histonas , N-Metiltransferasa de Histona-Lisina , Animales , Humanos , Ratones , Proteína BRCA1/metabolismo , Proteína BRCA1/genética , Línea Celular Tumoral , Cromatina/metabolismo , Roturas del ADN de Doble Cadena , Metilación de ADN , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Chaperonas de Histonas/metabolismo , Chaperonas de Histonas/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Metilación , Metiltransferasas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Tolerancia a Radiación/genéticaRESUMEN
Histone deacetylase 6 (HDAC6) mediates DNA damage signaling by regulating the mismatch repair and nucleotide excision repair pathways. Whether HDAC6 also mediates DNA double-strand break (DSB) repair is unclear. Here, we report that HDAC6 negatively regulates DSB repair in an enzyme activity-independent manner. In unstressed cells, HDAC6 interacts with H2A/H2A.X to prevent its interaction with the E3 ligase RNF168. Upon sensing DSBs, RNF168 rapidly ubiquitinates HDAC6 at lysine 116, leading to HDAC6 proteasomal degradation and a restored interaction between RNF168 and H2A/H2A.X. H2A/H2A.X is ubiquitinated by RNF168, precipitating the recruitment of DSB repair factors (including 53BP1 and BRCA1) to chromatin and subsequent DNA repair. These findings reveal novel regulatory machinery based on an HDAC6-RNF168 axis that regulates the H2A/H2A.X ubiquitination status. Interfering with this axis might be leveraged to disrupt a key mechanism of cancer cell resistance to genotoxic damage and form a potential therapeutic strategy for cancer.
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Reparación del ADN , Humanos , Línea Celular Tumoral , Daño del ADN , Histona Desacetilasa 6/genética , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinaciónRESUMEN
BACKGROUND: Inadequate DNA damage repair promotes aberrant differentiation of mammary epithelial cells. Mammary luminal cell fate is mainly determined by a few transcription factors including GATA3. We previously reported that GATA3 functions downstream of BRCA1 to suppress aberrant differentiation in breast cancer. How GATA3 impacts DNA damage repair preventing aberrant cell differentiation in breast cancer remains elusive. We previously demonstrated that loss of p18, a cell cycle inhibitor, in mice induces luminal-type mammary tumors, whereas depletion of either Brca1 or Gata3 in p18 null mice leads to basal-like breast cancers (BLBCs) with activation of epithelial-mesenchymal transition (EMT). We took advantage of these mutant mice to examine the role of Gata3 as well as the interaction of Gata3 and Brca1 in DNA damage repair in mammary tumorigenesis. RESULTS: Depletion of Gata3, like that of Brca1, promoted DNA damage accumulation in breast cancer cells in vitro and in basal-like breast cancers in vivo. Reconstitution of Gata3 improved DNA damage repair in Brca1-deficient mammary tumorigenesis. Overexpression of GATA3 promoted homologous recombination (HR)-mediated DNA damage repair and restored HR efficiency of BRCA1-deficient cells. Depletion of Gata3 sensitized tumor cells to PARP inhibitor (PARPi), and reconstitution of Gata3 enhanced resistance of Brca1-deficient tumor cells to PARP inhibitor. CONCLUSIONS: These results demonstrate that Gata3 functions downstream of BRCA1 to promote DNA damage repair and suppress dedifferentiation in mammary tumorigenesis and progression. Our findings suggest that PARP inhibitors are effective for the treatment of GATA3-deficient BLBCs.
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Neoplasias Mamarias Animales , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Ratones , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Daño del ADN , Reparación del ADN , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacologíaRESUMEN
A novel series of excited-state intramolecular proton transfer (ESIPT) emitters, namely, DPNA, DPNA-F, and DPNA-tBu, endowed with dual intramolecular hydrogen bonds, were designed and synthesized. In the condensed phase, DPNAs exhibit unmatched absorption and emission spectral features, where the minor 0-0 absorption peak becomes a major one in the emission. Detailed spectroscopic and dynamic approaches conclude fast ground-state equilibrium among enol-enol (EE), enol-keto (EK), and keto-keto (KK) isomers. The equilibrium ratio can be fine-tuned by varying the substitutions in DPNAs. Independent of isomers and excitation wavelength, ultrafast ESIPT takes place for all DPNAs, giving solely KK tautomer emission maximized at >650 nm. The spectral temporal evolution of ESIPT was resolved by a state-of-the-art technique, namely, the transient grating photoluminescence (TGPL), where the rate of EK* â KK* is measured to be (157 fs)-1 for DPNA-tBu, while a stepwise process is resolved for EE* â EK* â KK*, with a rate of EE* â EK* of (72 fs)-1. For all DPNAs, the KK tautomer emission shows a narrowband emission with high photoluminescence quantum yields (PLQY, â¼62% for DPNA in toluene) in the red, offering advantages to fabricate deep-red organic light-emitting diodes (OLED). The resulting OLEDs give high external quantum efficiency with a spectral full width at half-maximum (FWHM) as narrow as â¼40 nm centered at 666-670 nm for DPNAs, fully satisfying the BT. 2020 standard. The unique ESIPT properties and highly intense tautomer emission with a small fwhm thus establish a benchmark for reaching red narrowband organic electroluminescence.
RESUMEN
The fundamental role of cells in safeguarding the genome's integrity against DNA double-strand breaks (DSBs) is crucial for maintaining chromatin homeostasis and the overall genomic stability. Aberrant responses to DNA damage, known as DNA damage responses (DDRs), can result in genomic instability and contribute significantly to tumorigenesis. Unraveling the intricate mechanisms underlying DDRs following severe damage holds the key to identify therapeutic targets for cancer. Chromatin lysine acylation, encompassing diverse modifications such as acetylation, lactylation, crotonylation, succinylation, malonylation, glutarylation, propionylation, and butyrylation, has been extensively studied in the context of DDRs and chromatin homeostasis. Here, we delve into the modifying enzymes and the pivotal roles of lysine acylation and their crosstalk in maintaining chromatin homeostasis and genome integrity in response to DDRs. Moreover, we offer a comprehensive perspective and overview of the latest insights, driven primarily by chromatin acylation modification and associated regulators.
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A chemotherapy-based mobilization regimen in patients who mobilize poorly, based on etoposide, cytarabine and pegfilgrastim (EAP), has recently been introduced. The aim of this prospective study was to investigate the efficacy and safety of the EAP regimen in patients with poorly mobilizing multiple myeloma (MM) or lymphoma. This single-arm clinical trial was performed at eight public hospitals in China and was registered as a clinical trial (NCT05510089). The inclusion criteria were; (1) diagnosis of MM or lymphoma, (2) defined as a 'poor mobilizer' and (3) aged 18-75 years. The EAP regimen consisted of etoposide 75 mg/m2/day on days 1-2, cytarabine 300 mg/m2 every 12 h on days 1-2 and pegfilgrastim 6 mg on day 6. The primary endpoint of the study was the ratio of patients achieving adequate mobilization (≥2.0 × 106 CD34+ cells/kg). From 1 September 2022 to 15 August 2023, a total of 58 patients were enrolled, 53 (91.4%) achieved adequate mobilization, while 41 (70.7%) achieved optimal mobilization with a median number of cumulative collected CD34+ cells was 9.2 (range 2.1-92.7) × 106/kg and the median number of apheresis per patient of 1.2. The median time from administration of the EAP regimen to the first apheresis was 12 days. Approximately 8.6% of patients required plerixa for rescue, which was successful. Twelve (20.7%) of the 58 patients suffered grade 2-3 infections, while 25 (43.1%) required platelet transfusions. The duration of neutrophil and platelet engraftment was 11 days. In conclusion, these results suggest that the EAP mobilization regimen might be a promising option for poorly mobilizing patients with MM or lymphoma.
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Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina , Etopósido , Filgrastim , Movilización de Célula Madre Hematopoyética , Linfoma , Mieloma Múltiple , Polietilenglicoles , Humanos , Filgrastim/administración & dosificación , Filgrastim/uso terapéutico , Citarabina/administración & dosificación , Citarabina/uso terapéutico , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Femenino , Masculino , Etopósido/administración & dosificación , Etopósido/uso terapéutico , Adulto , Linfoma/tratamiento farmacológico , Linfoma/terapia , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/terapia , Estudios Prospectivos , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Movilización de Célula Madre Hematopoyética/métodos , Adulto Joven , AdolescenteRESUMEN
Cancer-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in the tumor microenvironment, which play important roles in regulating tumor progression and therapy resistance by transferring exosomes to cancer cells. However, how CAFs modulate esophageal squamous cell carcinoma (ESCC) progression and radioresistance remains incompletely understood. The expression of fibroblast activation protein (FAP) in CAFs was evaluated by immunohistochemistry in 174 ESCC patients who underwent surgery and 78 pretreatment biopsy specimens of ESCC patients who underwent definitive chemoradiotherapy. We sorted CAFs according to FAP expression, and the conditioned medium (CM) was collected to culture ESCC cells. The expression levels of several lncRNAs that were considered to regulate ESCC progression and/or radioresistance were measured in exosomes derived from FAP+ CAFs and FAP- CAFs. Subsequently, cell counting kit-8, 5-ethynyl-2'-deoxyuridine, transwell, colony formation, and xenograft assays were performed to investigate the functional differences between FAP+ CAFs and FAP- CAFs. Finally, a series of in vitro and in vivo assays were used to evaluate the effect of AFAP1-AS1 on radiosensitivity of ESCC cells. FAP expression in stromal CAFs was positively correlated with nerve invasion, vascular invasion, depth of invasion, lymph node metastasis, lack of clinical complete response and poor survival. Culture of ESCC cells with CM/FAP+ CAFs significantly increased cancer proliferation, migration, invasion and radioresistance, compared with culture with CM/FAP- CAFs. Importantly, FAP+ CAFs exert their roles by directly transferring the functional lncRNA AFAP1-AS1 to ESCC cells via exosomes. Functional studies showed that AFAP1-AS1 promoted radioresistance by enhancing DNA damage repair in ESCC cells. Clinically, high levels of plasma AFAP1-AS1 correlated with poor responses to dCRT in ESCC patients. Our findings demonstrated that FAP+ CAFs promoted radioresistance in ESCC cells through transferring exosomal lncRNA AFAP1-AS1; and may be a potential therapeutic target for ESCC treatment.
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Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome, and loss of autophagy has been linked to increased genome instability. Here, we report that loss of autophagy is coupled to reduced histone H2A ubiquitination after DNA damage. p62/SQSTM1, which accumulates in autophagy-defective cells, directly binds to and inhibits nuclear RNF168, an E3 ligase essential for histone H2A ubiquitination and DNA damage responses. As a result, DNA repair proteins such as BRCA1, RAP80, and Rad51 cannot be recruited to the sites of DNA double-strand breaks (DSBs), which impairs DSB repair. Moreover, nuclear-localized p62 increased the sensitivity of tumor cells to radiation both in vitro and in vivo, and this required its interaction with RNF168. Our findings indicate that autophagy-deficiency-induced p62 accumulation results in inhibition of histone ubiquitination and highlight the complex relationship between autophagy and the DNA damage response.
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Autofagia , Ensamble y Desensamble de Cromatina , Cromatina/metabolismo , Neoplasias Colorrectales/metabolismo , Roturas del ADN de Doble Cadena , Reparación del ADN , Proteína Sequestosoma-1/metabolismo , Ubiquitinación , Autofagia/efectos de la radiación , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Ensamble y Desensamble de Cromatina/efectos de la radiación , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/radioterapia , Reparación del ADN/efectos de la radiación , Células HCT116 , Histonas/metabolismo , Humanos , Interferencia de ARN , Tolerancia a Radiación , Proteína Sequestosoma-1/genética , Transducción de Señal , Transfección , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación/efectos de la radiaciónRESUMEN
PURPOSE: This study aimed to evaluate the cervical sagittal profile after the spontaneous compensation of global sagittal imbalance and analyze the associations between the changes in cervical sagittal alignment and spinopelvic parameters. METHODS: In this retrospective radiographic study, we analyzed 90 patients with degenerative lumbar stenosis (DLS) and sagittal imbalance who underwent short lumbar fusion (imbalance group). We used 60 patients with DLS and sagittal balance as the control group (balance group). Patients in the imbalance group were also divided into two groups according to the preoperative PI: low PI group (≤ 50°), high PI group (PI > 50°). We measured the spinal sagittal alignment parameters on the long-cassette standing lateral radiographs of the whole spine. We compared the changes of spinal sagittal parameters between pre-operation and post-operation. We observed the relationships between the changes in cervical profile and spinopelvic parameters. RESULTS: Sagittal vertical axis (SVA) occurred spontaneous compensation (p = 0.000) and significant changes were observed in cervical lordosis (CL) (p = 0.000) and cervical sagittal vertical axis (cSVA) (p = 0.023) after surgery in the imbalance group. However, there were no significant differences in the radiographic parameters from pre-operation to post-operation in the balance group. The variations in CL were correlated with the variations in SVA (R = 0.307, p = 0.041). The variations in cSVA were correlated with the variations in SVA (R=-0.470, p = 0.001). CONCLUSION: Cervical sagittal profile would have compensatory changes after short lumbar fusion. The spontaneous decrease in CL would occur in patients with DLS after the spontaneous compensation of global sagittal imbalance following one- or two-level lumbar fusion. The changes of cervical sagittal profile were related to the extent of the spontaneous compensation of SVA.
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Vértebras Cervicales , Lordosis , Vértebras Lumbares , Fusión Vertebral , Estenosis Espinal , Humanos , Fusión Vertebral/efectos adversos , Fusión Vertebral/métodos , Masculino , Femenino , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Vértebras Lumbares/cirugía , Vértebras Lumbares/diagnóstico por imagen , Vértebras Cervicales/cirugía , Vértebras Cervicales/diagnóstico por imagen , Estenosis Espinal/cirugía , Estenosis Espinal/diagnóstico por imagen , Lordosis/diagnóstico por imagen , Lordosis/cirugía , Equilibrio Postural/fisiología , RadiografíaRESUMEN
Ataxia telangiectasia and Rad3 related (ATR) activation after replication stress involves a cascade of reactions, including replication protein A (RPA) complex loading onto single-stranded DNA and ATR activator loading onto chromatin. The contribution of histone modifications to ATR activation, however, is unclear. Here, we report that H3K14 trimethylation responds to replication stress by enhancing ATR activation. First, we confirmed that H3K14 monomethylation, dimethylation, and trimethylation all exist in mammalian cells, and that both SUV39H1 and SETD2 methyltransferases can catalyze H3K14 trimethylation in vivo and in vitro. Interestingly, SETD2-mediated H3K14 trimethylation markedly increases in response to replication stress induced with hydroxyurea, a replication stress inducer. Under these conditions, SETD2-mediated H3K14me3 recruited the RPA complex to chromatin via a direct interaction with RPA70. The increase in H3K14me3 levels was abolished, and RPA loading was attenuated when SETD2 was depleted or H3K14 was mutated. Rather, the cells were sensitive to replication stress such that the replication forks failed to restart, and cell-cycle progression was delayed. These findings help us understand how H3K14 trimethylation links replication stress with ATR activation.
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Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Replicación del ADN , ADN/biosíntesis , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Proteína de Replicación A/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada/química , Proteínas de la Ataxia Telangiectasia Mutada/genética , ADN/química , ADN/genética , N-Metiltransferasa de Histona-Lisina/química , N-Metiltransferasa de Histona-Lisina/genética , Histonas/química , Histonas/genética , Humanos , Metilación , Metiltransferasas/química , Metiltransferasas/genética , Metiltransferasas/metabolismo , Proteína de Replicación A/química , Proteína de Replicación A/genética , Proteínas Represoras/química , Proteínas Represoras/genética , Proteínas Represoras/metabolismoRESUMEN
Currently, much research effort has been devoted to improving the exciton utilization efficiency and narrowing the emission spectra of ultraviolet (UV) fluorophores for organic light-emitting diode (OLED) applications, while almost no attention has been paid to optimizing their light out-coupling efficiency. Here, we developed a linear donor-acceptor-donor (D-A-D) triad, namely CDFDB, which possesses high-lying reverse intersystem crossing (hRISC) property. Thanks to its integrated narrowband UV photoluminescence (PL) (λPL: 397â nm; FWHM: 48â nm), moderate PL quantum yield (ÏPL: 72 %, Tol), good triplet hot exciton (HE) conversion capability, and large horizontal dipole ratio (Θ//: 92 %), the OLEDs based on CDFDB not only can emit UV electroluminescence with relatively good color purity (λEL: 398â nm; CIEx,y: 0.161, 0.040), but also show a record maximum external quantum efficiency (EQEmax) of 12.0 %. This study highlights the important role of horizontal dipole orientation engineering in the molecular design of HE UV-OLED fluorophores.
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Overcoming the trade-off between short-circuited current (Jsc) and open-circuited voltage (Voc) is important to achieving high-efficiency organic solar cells (OSCs). Previous works modulated energy gap between Frenkel local exciton (LE) and charge-transfer (CT) exciton, which is served as driving force of exciton splitting. Differently, our current work focuses on modulation of LE-CT excitonic coupling (tLE-CT) via a simple but effective strategy that the 2-chlorothiophene (2Cl-Th) solvent is utilized in treatment of OSC active-layer films. The results of our experimental measurements and theoretical simulations demonstrated that 2Cl-Th solvent initiates the tighter intermolecular interactions with non-fullerene acceptor in comparison with that of traditional chlorobenzene solvent, thus suppressing the acceptor's over-aggregation and retarding the acceptor crystallization with reduced trap. Importantly, the resulted shorter distances between donor and acceptor molecules in the 2Cl-Th treated blend efficiently strengthen tLE-CT, which not only promotes the exciton splitting but also reduces non-radiative recombination. The champion efficiencies of 19.8% (small-area) with a superior operational reliability (T80: 586 hours) and 17.0% (large-area) were yielded in 2Cl-Th treated cells. This work provided a new insight into modulating the exciton dynamics to overcome the trade-off between Jsc and Voc, which can productively promote the development of OSC field.
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Achieving both high power conversion efficiency (PCE) and device stability is a major challenge for the practical development of organic solar cells (OSCs). Herein, three non-fully conjugated dimerized giant acceptors (named 2Y-sites, including wing-site-linked 2Y-wing, core-site-linked 2Y-core, and end-site-linked 2Y-end) are developed. They share the similar monomer precursors but have different alkyl-linked sites, offering the fine-tuned molecular absorption, packing, glass transition temperature, and carrier mobility. Among their binary active layers, D18/2Y-wing has better miscibility, leading to optimized morphology and more efficient charge transfer compared to D18/2Y-core and D18/2Y-end. Therefore, the D18/2Y-wing-based OSCs achieve a superior PCE of 17.73 %, attributed to enhanced photocurrent and fill factor. Furthermore, the D18/2Y-wing-based OSCs exhibit a balance of high PCE and improved stability, distinguishing them within the 2Y-sites. Building on the success of 2Y-wing in binary systems, we extend its application to ternary OSCs by pairing it with the near-infrared absorbing D18/BS3TSe-4F host. Thanks to the complementary absorption within 300-970â nm and further optimized morphology, ternary OSCs obtain a higher PCE of 19.13 %, setting a new efficiency benchmark for the dimer-derived OSCs. This approach of alkyl-linked site engineering for constructing dimerized giant acceptors presents a promising pathway to improve both PCE and stability of OSCs.
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FOXO1, a transcription factor downstream of the insulin/insulin like growth factor axis, has been linked to protein degradation. Elevated expression of FOXO orthologs can also prevent the aggregation of cytosine adenine guanine (CAG)-repeat disease causing polyglutamine (polyQ) proteins but whether FOXO1 targets mutant proteins for degradation is unclear. Here, we show that increased expression of FOXO1 prevents toxic polyQ aggregation in human cells while reducing FOXO1 levels has the opposite effect and accelerates it. Although FOXO1 indeed stimulates autophagy, its effect on polyQ aggregation is independent of autophagy, ubiquitin-proteasome system (UPS) mediated protein degradation and is not due to a change in mutant polyQ protein turnover. Instead, FOXO1 specifically downregulates protein synthesis rates from expanded pathogenic CAG repeat transcripts. FOXO1 orchestrates a change in the composition of proteins that occupy mutant expanded CAG transcripts, including the recruitment of IGF2BP3. This mRNA binding protein enables a FOXO1 driven decrease in pathogenic expanded CAG transcript- and protein levels, thereby reducing the initiation of amyloidogenesis. Our data thus demonstrate that FOXO1 not only preserves protein homeostasis at multiple levels, but also reduces the accumulation of aberrant RNA species that may co-contribute to the toxicity in CAG-repeat diseases.
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Proteína Forkhead Box O1/genética , Péptidos/genética , Agregación Patológica de Proteínas/genética , Proteínas de Unión al ARN/genética , Adenina/metabolismo , Proteínas Amiloidogénicas , Autofagia/genética , Citosina/metabolismo , Proteína Forkhead Box O1/biosíntesis , Regulación de la Expresión Génica/genética , Guanina/metabolismo , Células HEK293 , Humanos , Proteínas Mutantes/genética , Péptidos/toxicidad , Agregación Patológica de Proteínas/patología , Biosíntesis de Proteínas/genética , Proteolisis , ARN Mensajero/genética , Repeticiones de Trinucleótidos/genéticaRESUMEN
To reducing chemotherapy-related toxicity, the chemo-free regimens become a new trend of Ph + ALL treatment. Therefore, we conducted a phase 2 trial of dasatinib plus prednisone, as induction (Course I) and early consolidation (Courses II and III) treating newly diagnosed Ph + ALL. The trial was registered at www.chictr.org.cn, ChiCTR2000038053. Forty-one patients were enrolled from 15 hospitals. The complete remission (CR) was 95% (39/41), including two elderly induction deaths. By the end of Course III, 25.6% (10/39) of patients achieved a complete molecular response. With a median follow-up of 15.4 months, 2-year disease-free survival (DFS) were 100% and 33% for patients who receiving haematopoietic stem cell transplantation (HSCT) at CR1 and receiving chemotherapy alone respectively. When censored at time of HSCT, 2-year DFS were 51% and 45% for young and elderly patients (p = 0.987). 2-year overall survival were 45%, 86% and 100% for patients without HSCT, receiving HSCT after relapse and receiving HSCT at CR1 respectively. A total of 12 patients had marrow recurrences and one had CNS relapse, with 38% occurred early (between Courses I and III). IKZF1 gene deletion was shown to be associated with relapse (p = 0.019). This chemo-free induction and early consolidation regimen was efficacious and well-tolerated in de novo Ph + ALL. Allogeneic HSCT conferred definite survival advantage after chemo-free induction.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Adulto , Anciano , Dasatinib/efectos adversos , Prednisona/efectos adversos , Cromosoma Filadelfia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Supervivencia sin Enfermedad , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inducción de Remisión , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Ternary polymer solar cells(PSCs) have been identified as an effective approach to improving power conversion efficiency (PCE) of binary PSCs. However, most of the third component, especially Y-series non-fullerene acceptors, is a fused ring acceptor which often requires a rather tedious synthesis and the use of hazardous organostannane reagents. In this work, two nonfused ring acceptors IOEH-4F and IOEH-N2F are synthesized by a green synthetic route and incorporated into PM6:Y6 blend. Encouragingly, the IOEH-4F and IOEH-N2F-based ternary PSCs exhibited more efficient charge transfer, exciton separation, and lower energy loss than PM6:Y6-based PSCs. And the IOEH-4F and IOEH-N2F-based ternary PSCs achieved an impressive PCE of 17.80% and 18.13%, respectively, which are higher than that of PM6:Y6 based PSCs (16.18%). Notably, these PCE values are also the highest PCEs for ternary PSCs including non-fused ring acceptors. Importantly, even when the IOEH-N2F:Y6 ratios increased from 0.05:1.2 to 0.50:1.2, the PCE of IOEH-N2F-based ternary PSCs (16.70%) are still higher than that of PM6:Y6 based PSCs, indicating the great potential for cost saving. It is believed that the findings will help the design of better nonfused ring acceptors and the optimization of corresponding ternary PSCs with cost-saving advantage.