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1.
Mol Cell ; 81(14): 2960-2974.e7, 2021 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-34111398

RESUMEN

The transition of oxidized 5-methylcytosine (5mC) intermediates into the base excision repair (BER) pipeline to complete DNA demethylation remains enigmatic. We report here that UHRF2, the only paralog of UHRF1 in mammals that fails to rescue Uhrf1-/- phenotype, is physically and functionally associated with BER complex. We show that UHRF2 is allosterically activated by 5-hydroxymethylcytosine (5hmC) and acts as a ubiquitin E3 ligase to catalyze K33-linked polyubiquitination of XRCC1. This nonproteolytic action stimulates XRCC1's interaction with the ubiquitin binding domain-bearing RAD23B, leading to the incorporation of TDG into BER complex. Integrative epigenomic analysis in mouse embryonic stem cells reveals that Uhrf2-fostered TDG-RAD23B-BER complex is functionally linked to the completion of DNA demethylation at active promoters and that Uhrf2 ablation impedes DNA demethylation on latent enhancers that undergo poised-to-active transition during neuronal commitment. Together, these observations highlight an essentiality of 5hmC-switched UHRF2 E3 ligase activity in commissioning the accomplishment of active DNA demethylation.


Asunto(s)
5-Metilcitosina/análogos & derivados , Regulación Alostérica/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación/genética , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , 5-Metilcitosina/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Desmetilación del ADN , Metilación de ADN/genética , Reparación del ADN/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Células HEK293 , Humanos , Células MCF-7 , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas/genética , Unión Proteica/genética
2.
EMBO J ; 40(19): e107974, 2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34459501

RESUMEN

Identification of the driving force behind malignant transformation holds the promise to combat the relapse and therapeutic resistance of cancer. We report here that the single nucleotide polymorphism (SNP) rs4971059, one of 65 new breast cancer risk loci identified in a recent genome-wide association study (GWAS), functions as an active enhancer of TRIM46 expression. Recreating the G-to-A polymorphic switch caused by the SNP via CRISPR/Cas9-mediated homologous recombination leads to an overt upregulation of TRIM46. We find that TRIM46 is a ubiquitin ligase that targets histone deacetylase HDAC1 for ubiquitination and degradation and that the TRIM46-HDAC1 axis regulates a panel of genes, including ones critically involved in DNA replication and repair. Consequently, TRIM46 promotes breast cancer cell proliferation and chemoresistance in vitro and accelerates tumor growth in vivo. Moreover, TRIM46 is frequently overexpressed in breast carcinomas, and its expression is correlated with lower HDAC1 expression, higher histological grades, and worse prognosis of the patients. Together, our study links SNP rs4971059 to replication and to breast carcinogenesis and chemoresistance and support the pursuit of TRIM46 as a potential target for breast cancer intervention.


Asunto(s)
Alelos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Resistencia a Antineoplásicos/genética , Histona Desacetilasa 1/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Polimorfismo de Nucleótido Simple , Línea Celular Tumoral , Proliferación Celular/genética , Reparación del ADN , Replicación del ADN , Elementos de Facilitación Genéticos , Femenino , Humanos , Intrones , Proteínas del Tejido Nervioso/genética , Unión Proteica , Proteolisis , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación
3.
Mol Cell ; 67(5): 853-866.e5, 2017 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-28803779

RESUMEN

Lysine crotonylation (Kcr) is a newly identified histone modification that is associated with active transcription in mammalian cells. Here we report that the chromodomain Y-like transcription corepressor CDYL negatively regulates histone Kcr by acting as a crotonyl-CoA hydratase to convert crotonyl-CoA to ß-hydroxybutyryl-CoA. We showed that the negative regulation of histone Kcr by CDYL is intrinsically linked to its transcription repression activity and functionally implemented in the reactivation of sex chromosome-linked genes in round spermatids and genome-wide histone replacement in elongating spermatids. Significantly, Cdyl transgenic mice manifest dysregulation of histone Kcr and reduction of male fertility with a decreased epididymal sperm count and sperm cell motility. Our study uncovers a biochemical pathway in the regulation of histone Kcr and implicates CDYL-regulated histone Kcr in spermatogenesis, adding to the understanding of the physiology of male reproduction and the mechanism of the spermatogenic failure in AZFc (Azoospermia Factor c)-deleted infertile men.


Asunto(s)
Acilcoenzima A/metabolismo , Proteínas Co-Represoras/metabolismo , Enoil-CoA Hidratasa/metabolismo , Histona Acetiltransferasas/metabolismo , Histonas/metabolismo , Infertilidad Masculina/enzimología , Procesamiento Proteico-Postraduccional , Proteínas/metabolismo , Espermatogénesis , Espermatozoides/enzimología , Testículo/enzimología , Animales , Proteínas Co-Represoras/genética , Enoil-CoA Hidratasa/genética , Fertilidad , Predisposición Genética a la Enfermedad , Células HeLa , Histona Acetiltransferasas/genética , Humanos , Hidroliasas , Infertilidad Masculina/genética , Infertilidad Masculina/patología , Infertilidad Masculina/fisiopatología , Cinética , Lisina , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Dominios Proteicos , Proteínas/genética , Interferencia de ARN , Células Sf9 , Recuento de Espermatozoides , Motilidad Espermática , Espermatozoides/patología , Testículo/patología , Testículo/fisiopatología , Transfección
4.
Proc Natl Acad Sci U S A ; 119(6)2022 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-35105803

RESUMEN

BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including c-MYC and BCL2 As such, BRD4 inhibitors are being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here, we report that BRD4 unexpectedly interacts with the LSD1/NuRD complex and colocalizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small-molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant genes, but long-time treatment or destabilization of LSD1 by PELI1 decommissions the BRD4/LSD1/NuRD complex, leading to resistance to JQ1 as well as to a broad spectrum of therapeutic compounds. Consistently, PELI1 is up-regulated in breast carcinomas, its level is negatively correlated with that of LSD1, and the expression level of the BRD4/LSD1/NuRD complex-restricted genes is strongly correlated with a worse overall survival of breast cancer patients. Together, our study uncovers a functional duality of BRD4 in super-enhancer organization of transcription activation and repression linking to oncogenesis and chemoresistance, respectively, supporting the pursuit of a combined targeting of BRD4 and PELI1 in effective treatment of breast cancer.


Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Neoplasias/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Proteínas de Ciclo Celular/genética , Femenino , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Humanos , Células MCF-7 , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Proteínas de Neoplasias/genética , Factores de Transcripción/genética
5.
Cell ; 138(4): 660-72, 2009 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-19703393

RESUMEN

Lysine-specific demethylase 1 (LSD1) exerts pathway-specific activity in animal development and has been linked to several high-risk cancers. Here, we report that LSD1 is an integral component of the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex. Transcriptional target analysis revealed that the LSD1/NuRD complexes regulate several cellular signaling pathways including TGFbeta1 signaling pathway that are critically involved in cell proliferation, survival, and epithelial-to-mesenchymal transition. We demonstrated that LSD1 inhibits the invasion of breast cancer cells in vitro and suppresses breast cancer metastatic potential in vivo. We found that LSD1 is downregulated in breast carcinomas and that its level of expression is negatively correlated with that of TGFbeta1. Our data provide a molecular basis for the interplay of histone demethylation and deacetylation in chromatin remodeling. By enlisting LSD1, the NuRD complex expands its chromatin remodeling capacity to include ATPase, histone deacetylase, and histone demethylase.


Asunto(s)
Neoplasias de la Mama/metabolismo , Histona Desacetilasas/metabolismo , Metástasis de la Neoplasia/genética , Oxidorreductasas N-Desmetilantes/metabolismo , Animales , Línea Celular Tumoral , Ensamble y Desensamble de Cromatina , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Células HeLa , Histona Demetilasas , Humanos , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2 , Ratones , Ratones SCID , Trasplante de Neoplasias , Nucleosomas/metabolismo , Oxidorreductasas N-Desmetilantes/química , Fragmentos de Péptidos/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo
6.
EMBO Rep ; 22(7): e52036, 2021 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-34114325

RESUMEN

Dysregulation of lipid metabolism could lead to the development of metabolic disorders. We report here that the F-box protein JFK promotes excessive lipid accumulation in adipose tissue and contributes to the development of metabolic syndrome. JFK transgenic mice develop spontaneous obesity, accompanied by dyslipidemia, hyperglycemia, and insulin resistance, phenotypes that are further exacerbated under high-fat diets. In contrast, Jfk knockout mice are lean and resistant to diet-induced metabolic malfunctions. Liver-specific reconstitution of JFK expression in Jfk knockout mice leads to hepatic lipid accumulation resembling human hepatic steatosis and nonalcoholic fatty liver disease. We show that JFK interacts with and destabilizes ING5 through assembly of the SCF complex. Integrative transcriptomic and genomic analysis reveals that the SCFJFK -ING5 axis interferes with AMPK activity and fatty acid ß-oxidation, leading to the suppression of hepatic lipid catabolism. Significantly, JFK is upregulated and AMPKα1 is down-regulated in liver tissues from NAFLD patients. These results reveal that SCFJFK is a bona fide E3 ligase for ING5 and link the SCFJFK -ING5 axis to the development of obesity and metabolic syndrome.


Asunto(s)
Resistencia a la Insulina , Síndrome Metabólico , Enfermedad del Hígado Graso no Alcohólico , Animales , Dieta Alta en Grasa/efectos adversos , Humanos , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Síndrome Metabólico/genética , Síndrome Metabólico/metabolismo , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/genética , Obesidad/metabolismo , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo
7.
Genes Dev ; 29(6): 672-85, 2015 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-25792601

RESUMEN

Loss of function/dysregulation of inhibitor of growth 4 (ING4) and hyperactivation of NF-κB are frequent events in many types of human malignancies. However, the molecular mechanisms underlying these remarkable aberrations are not understood. Here, we report that ING4 is physically associated with JFK. We demonstrated that JFK targets ING4 for ubiquitination and degradation through assembly of an Skp1-Cul1-F-box (SCF) complex. We showed that JFK-mediated ING4 destabilization leads to the hyperactivation of the canonical NF-κB pathway and promotes angiogenesis and metastasis of breast cancer. Significantly, the expression of JFK is markedly up-regulated in breast cancer, and the level of JFK is negatively correlated with that of ING4 and positively correlated with an aggressive clinical behavior of breast carcinomas. Our study identified SCF(JFK) as a bona fide E3 ligase for ING4 and unraveled the JFK-ING4-NF-κB axis as an important player in the development and progression of breast cancer, supporting the pursuit of JFK as a potential target for breast cancer intervention.


Asunto(s)
Neoplasias de la Mama/enzimología , Neoplasias de la Mama/fisiopatología , Proteínas de Ciclo Celular/metabolismo , Proteínas F-Box/metabolismo , Proteínas de Homeodominio/metabolismo , Neovascularización Patológica/enzimología , Proteínas Supresoras de Tumor/metabolismo , Neoplasias de la Mama/irrigación sanguínea , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Complejos Multiproteicos , FN-kappa B/metabolismo , Metástasis de la Neoplasia , Neovascularización Patológica/genética , Proteolisis , Transducción de Señal , Ubiquitinación
8.
Mol Cell ; 55(3): 482-94, 2014 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-25018020

RESUMEN

Histone H3K4 demethylase LSD1 plays an important role in stem cell biology, especially in the maintenance of the silencing of differentiation genes. However, how the function of LSD1 is regulated and the differentiation genes are derepressed are not understood. Here, we report that elimination of LSD1 promotes embryonic stem cell (ESC) differentiation toward neural lineage. We showed that the destabilization of LSD1 occurs posttranscriptionally via the ubiquitin-proteasome pathway by an E3 ubiquitin ligase, Jade-2. We demonstrated that Jade-2 is a major LSD1 negative regulator during neurogenesis in vitro and in vivo in both mouse developing cerebral cortices and zebra fish embryos. Apparently, Jade-2-mediated degradation of LSD1 acts as an antibraking system and serves as a quick adaptive mechanism for re-establishing epigenetic landscape without more laborious transcriptional regulations. As a potential anticancer strategy, Jade-2-mediated LSD1 degradation could potentially be used in neuroblastoma cells to induce differentiation toward postmitotic neurons.


Asunto(s)
Células Madre Embrionarias/metabolismo , Histona Demetilasas/metabolismo , Neuroblastoma/metabolismo , Neurogénesis , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Diferenciación Celular , Línea Celular Tumoral , Epigénesis Genética , Regulación del Desarrollo de la Expresión Génica , Células HeLa , Histona Demetilasas/genética , Humanos , Ratones , Neuroblastoma/fisiopatología , Oxidorreductasas N-Desmetilantes/genética , Oxidorreductasas N-Desmetilantes/metabolismo , Ubiquitina-Proteína Ligasas/genética , Pez Cebra/embriología , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo
9.
Nucleic Acids Res ; 47(18): 9721-9740, 2019 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-31504778

RESUMEN

How chromatin dynamics is regulated to ensure efficient DNA repair remains to be understood. Here, we report that the ubiquitin-specific protease USP11 acts as a histone deubiquitinase to catalyze H2AK119 and H2BK120 deubiquitination. We showed that USP11 is physically associated with the chromatin remodeling NuRD complex and functionally involved in DNA repair process. We demonstrated that USP11-mediated histone deubiquitination and NuRD-associated histone deacetylation coordinate to allow timely termination of DNA repair and reorganization of the chromatin structure. As such, USP11 is involved in chromatin condensation, genomic stability, and cell survival. Together, these observations indicate that USP11 is a chromatin modifier critically involved in DNA damage response and the maintenance of genomic stability.


Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Reparación del ADN/genética , Enzimas Desubicuitinizantes/genética , Tioléster Hidrolasas/genética , Supervivencia Celular/genética , Cromatina/genética , Roturas del ADN de Doble Cadena , Daño del ADN/genética , Inestabilidad Genómica/genética , Células HEK293 , Histonas/genética , Humanos , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Procesamiento Proteico-Postraduccional/genética , Ubiquitinación/genética
10.
Mol Cell ; 44(1): 39-50, 2011 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-21981917

RESUMEN

Histone acetyltransferases (HATs) are an essential regulatory component in chromatin biology. Unlike A-type HATs, which are found in the nucleus and utilize nucleosomal histones as substrates and thus primarily function in transcriptional regulation, B-type HATs have been characterized as cytoplasmic enzymes that catalyze the acetylation of free histones. Here, we report on a member of the GCN5-related N-acetyltransferase superfamily and another B-type HAT, HAT4. Interestingly, HAT4 is localized in the Golgi apparatus and displays a substrate preference for lysine residues of free histone H4, including H4K79 and H4K91, that reside in the globular domain of H4. Significantly, HAT4 depletion impaired nucleosome assembly, inhibited cell proliferation, sensitized cells to DNA damage, and induced cell apoptosis. Our data indicate that HAT4 is an important player in the organization and function of the genome and may contribute to the diversity and complexity of higher eukaryotic organisms.


Asunto(s)
Cromatina/química , Citoplasma/metabolismo , Regulación Enzimológica de la Expresión Génica , Histona Acetiltransferasas/metabolismo , Histonas/química , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proliferación Celular , Clonación Molecular , Daño del ADN , Aparato de Golgi/metabolismo , Humanos , Nucleosomas/metabolismo , Estructura Terciaria de Proteína
11.
J Biol Chem ; 292(44): 18113-18128, 2017 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-28878014

RESUMEN

The de novo assembly and post-splicing reassembly of the U4/U6.U5 tri-snRNP remain to be investigated. We report here that ZIP, a protein containing a CCCH-type zinc finger and a G-patch domain, as characterized by us previously, regulates pre-mRNA splicing independent of RNA binding. We found that ZIP physically associates with the U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP). Remarkably, the ZIP-containing tri-snRNP, which has a sedimentation coefficient of ∼35S, is a tri-snRNP that has not been described previously. We also found that the 35S tri-snRNP contains hPrp24, indicative of a state in which the U4/U6 di-snRNP is integrating with the U5 snRNP. We found that the 35S tri-snRNP is enriched in the Cajal body, indicating that it is an assembly intermediate during 25S tri-snRNP maturation. We showed that the 35S tri-snRNP also contains hPrp43, in which ATPase/RNA helicase activities are stimulated by ZIP. Our study identified, for the first time, a tri-snRNP intermediate, shedding new light on the de novo assembly and recycling of the U4/U6.U5 tri-snRNP.


Asunto(s)
Empalme Alternativo , Antígenos de Neoplasias/metabolismo , Biogénesis de Organelos , ARN Helicasas/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas Represoras/metabolismo , Empalmosomas/metabolismo , Proteasas Ubiquitina-Específicas/metabolismo , Antígenos de Neoplasias/química , Antígenos de Neoplasias/genética , Cuerpos Enrollados/química , Cuerpos Enrollados/enzimología , Cuerpos Enrollados/metabolismo , Células HeLa , Humanos , Inmunoprecipitación , Células MCF-7 , Microscopía Electrónica de Transmisión , Microscopía Fluorescente , Peso Molecular , Mutación , Coloración Negativa , Oligopéptidos/genética , Oligopéptidos/metabolismo , Multimerización de Proteína , Estabilidad Proteica , ARN Helicasas/química , ARN Helicasas/genética , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/genética , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Represoras/química , Proteínas Represoras/genética , Ribonucleoproteína Nuclear Pequeña U5/química , Ribonucleoproteína Nuclear Pequeña U5/metabolismo , Empalmosomas/química , Empalmosomas/enzimología , Proteasas Ubiquitina-Específicas/química , Proteasas Ubiquitina-Específicas/genética
12.
PLoS Biol ; 12(3): e1001819, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24667498

RESUMEN

Jumonji domain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins. Compared to other members of the family, the cellular activity of JMJD6 is still not clearly defined and its biological function is still largely unexplored. Here we report that JMJD6 is physically associated with the tumor suppressor p53. We demonstrated that JMJD6 acts as an α-ketoglutarate- and Fe(II)-dependent lysyl hydroxylase to catalyze p53 hydroxylation. We found that p53 indeed exists as a hydroxylated protein in vivo and that the hydroxylation occurs mainly on lysine 382 of p53. We showed that JMJD6 antagonizes p53 acetylation, promotes the association of p53 with its negative regulator MDMX, and represses transcriptional activity of p53. Depletion of JMJD6 enhances p53 transcriptional activity, arrests cells in the G1 phase, promotes cell apoptosis, and sensitizes cells to DNA damaging agent-induced cell death. Importantly, knockdown of JMJD6 represses p53-dependent colon cell proliferation and tumorigenesis in vivo, and significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results reveal a novel posttranslational modification for p53 and support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.


Asunto(s)
Neoplasias del Colon/genética , Histona Demetilasas con Dominio de Jumonji/fisiología , Proteína p53 Supresora de Tumor/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Carcinogénesis/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hidroxilación , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Estudios Retrospectivos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/fisiología
13.
Proc Natl Acad Sci U S A ; 111(19): 7096-101, 2014 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-24778210

RESUMEN

Maintenance of genomic stability is essential for normal organismal development and is vital to prevent diseases such as cancer. As genetic information is packaged into chromatin, it has become increasingly clear that the chromatin environment plays an important role in DNA damage response. However, how DNA repair is controlled by epigenetic mechanisms is not fully understood. Here we report the identification and characterization of lysine-specific histone demethylase 5B (KDM5B), a member of the JmjC domain-containing histone demethylases, as an important player in multiple aspects of DNA double-strand break (DSB) response in human cells. We found that KDM5B becomes enriched in DNA-damage sites after ironizing radiation and endonuclease treatment in a poly(ADP ribose) polymerase 1- and histone variant macroH2A1.1-dependent manner. We showed that KDM5B is required for efficient DSB repair and for the recruitment of Ku70 and BRCA1, the essential component of nonhomologous end-joining and homologous recombination, respectively. Significantly, KDM5B deficiency disengages the DNA repair process, promotes spontaneous DNA damage, activates p53 signaling, and sensitizes cells to genotoxic insults. Our results suggest that KDM5B is a bona fide DNA damage response protein and indicate that KDM5B is an important genome caretaker and a critical regulator of genome stability, adding to the understanding of the roles of epigenetics in the maintenance of genetic fidelity.


Asunto(s)
Inestabilidad Genómica/fisiología , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Células Cultivadas , Daño del ADN/fisiología , Reparación del ADN/fisiología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células HEK293 , Histonas/metabolismo , Humanos , Autoantígeno Ku , Células MCF-7 , Metilación , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , ARN Interferente Pequeño/genética , Transducción de Señal/fisiología
14.
Annu Rev Physiol ; 75: 225-40, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23043248

RESUMEN

Estrogen exhibits a broad spectrum of physiological functions ranging from regulation of the menstrual cycle and reproduction to modulation of bone density, brain function, and cholesterol mobilization. Despite the beneficial actions of endogenous estrogen, sustained exposure to exogenous estrogen is a well-established risk factor for various cancers. We summarize our current understanding of the molecular mechanisms of estrogen signaling in normal and cancer cells and discuss the major challenges to existing antiestrogen therapies.


Asunto(s)
Estrógenos/fisiología , Neoplasias/fisiopatología , Transducción de Señal/fisiología , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/fisiopatología , Neoplasias Endometriales/epidemiología , Neoplasias Endometriales/fisiopatología , Estrógenos/efectos adversos , Femenino , Humanos , Receptores de Estrógenos/fisiología , Factores de Riesgo
15.
EMBO J ; 31(1): 110-23, 2012 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-21983900

RESUMEN

SET8 is implicated in transcriptional regulation, heterochromatin formation, genomic stability, cell-cycle progression, and development. As such, it is predicted that SET8 might be involved in the development and progression of tumour. However, whether and how SET8 might be implicated in tumourigenesis is currently unknown. Here, we report that SET8 is physically associated with TWIST, a master regulator of epithelial-mesenchymal transition (EMT). We demonstrated that SET8 and TWIST are functionally interdependent in promoting EMT and enhancing the invasive potential of breast cancer cells in vitro and in vivo. We showed that SET8 acts as a dual epigenetic modifier on the promoters of the TWIST target genes E-cadherin and N-cadherin via its H4K20 monomethylation activity. Significantly, in breast carcinoma samples, SET8 expression is positively correlated with metastasis and the expression of TWIST and N-cadherin and negatively correlated with E-cadherin. Together, our experiments revealed a novel role for SET8 in tumour invasion and metastasis and provide a molecular mechanism underlying TWIST-promoted EMT, suggesting SET8 as a potential target for intervention of the metastasis of breast cancer.


Asunto(s)
Transición Epitelial-Mesenquimal , N-Metiltransferasa de Histona-Lisina/metabolismo , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada con Twist/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Femenino , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Invasividad Neoplásica , Proteínas Nucleares/genética , Transcripción Genética , Proteína 1 Relacionada con Twist/genética
16.
J Neurosci ; 34(13): 4494-508, 2014 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-24671995

RESUMEN

Dendritic arborization is one of the key determinants of precise circuits for information processing in neurons. Unraveling the molecular mechanisms underlying dendrite morphogenesis is critical to understanding the establishment of neuronal connections. Here, using gain- and loss-of-function approaches, we defined the chromodomain protein and transcription corepressor chromodomain Y-like (CDYL) protein as a negative regulator of dendrite morphogenesis in rat/mouse hippocampal neurons both in vitro and in vivo. Overexpressing CDYL decreased, whereas knocking it down increased, the dendritic complexity of the primary cultured rat neurons. High-throughput DNA microarray screening identified a number of CDYL downstream target genes, including the brain-derived neurotrophic factor (BDNF). Knock-down of CDYL in neuronal cells led to increased expression of BDNF, which is primarily responsible for CDYL's effects on dendrite patterns. Mechanistically, CDYL interacts with EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), directly and recruits the H3K27 methyltransferase activity to the promoter region of the BDNF gene. In doing so, CDYL and EZH2 coordinately restrict dendrite morphogenesis in an interdependent manner. Finally, we found that neural activity increased dendritic complexity through degradation of CDYL protein to unleash its inhibition on BDNF. These results link, for the first time, the epigenetic regulators CDYL and EZH2 to dendrite morphogenesis and might shed new light on our understanding of the regulation of the neurodevelopment.


Asunto(s)
Dendritas/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Neuronas/citología , Complejo Represivo Polycomb 2/metabolismo , Proteínas/metabolismo , Animales , Células Cultivadas , Proteínas Co-Represoras , Embrión de Mamíferos , Proteína Potenciadora del Homólogo Zeste 2 , Femenino , Regulación del Desarrollo de la Expresión Génica/genética , Hipocampo/citología , Humanos , Hidroliasas , Masculino , Ratones , Ratones Endogámicos ICR , Ratones Transgénicos , Mutación/genética , Complejo Represivo Polycomb 2/genética , Proteínas/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ratas , Factores de Tiempo
17.
FASEB J ; 28(11): 4821-34, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25063848

RESUMEN

ATP-binding cassette (ABC) transporters are implicated in a diverse range of physiological and pathophysiological processes, such as cholesterol and lipid transportation and multidrug resistance. Despite the considerable efforts made in understanding of the cellular function of ABC proteins, the regulation mechanism of this type of protein is still poorly defined. Here we report the identification and functional characterization of a novel ATPase protein, protein associated with ABC transporters (PAAT), in humans. PAAT contains a nucleotide-binding domain (NBD)-like domain and a signal for intramitochondrial sorting. We showed that PAAT is localized in both the cytoplasm and the mitochondria and has an intrinsic ATPase activity. PAAT physically interacts with the 3 known mitochondrial inner membrane ABC proteins, ABCB7, ABCB8, and ABCB10, but not ABCB1, ABCB6, or ABCG2, and functionally regulates the transport of ferric nutrients and heme biosynthesis. Significantly, PAAT deficiency promotes cell death, reduces mitochondrial potential, and sensitizes mitochondria to oxidative stress-induced DNA damages. Our experiments revealed that PAAT is a novel ATPase and a trans-regulator of mitochondrial ABC transporters that plays an important role in the maintenance of mitochondrial homeostasis and cell survival.


Asunto(s)
Sistema de Transporte de Aminoácidos A/metabolismo , Homeostasis/fisiología , Mitocondrias/metabolismo , Células Cultivadas , Humanos , Unión Proteica , Transporte de Proteínas/fisiología
18.
Nat Rev Cancer ; 6(5): 360-8, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16633364

RESUMEN

Endometrial cancer is the most common gynaecological cancer, and is associated with endometrial hyperplasia, unopposed oestrogen exposure and adjuvant therapy for breast cancer using selective oestrogen-receptor modulators (SERMs), particularly tamoxifen. Oestrogen and SERMs are thought to be involved in endometrial carcinogenesis through their effects on transcriptional regulation. Ultimately, oestrogen and SERMs affect the transduction of cellular signalling pathways that govern cell growth and proliferation, through downstream effectors such as PAX2 (paired box 2).


Asunto(s)
Transformación Celular Neoplásica/efectos de los fármacos , Neoplasias Endometriales/inducido químicamente , Estrógenos/efectos adversos , Moduladores Selectivos de los Receptores de Estrógeno/efectos adversos , Animales , Transformación Celular Neoplásica/patología , Neoplasias Endometriales/patología , Estrógenos/farmacología , Femenino , Humanos , Factor de Transcripción PAX2/genética , Factor de Transcripción PAX2/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/farmacología
19.
J Biol Chem ; 288(27): 19633-42, 2013 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-23720754

RESUMEN

SET8 (SET domain containing 8) is a histone H4 lysine 20 (H4K20)-specific monomethyltransferase in higher eukaryotes that exerts diverse functions in transcription regulation, DNA repair, tumor metastasis, and genome integrity. The activity of SET8 is tightly controlled during cell cycle through post-translational modifications, including ubiquitination, phosphorylation, and sumoylation. However, how the expression of SET8 is regulated is not fully understood. Here, we report that microRNA-7 is a negative regulator of SET8. We demonstrated that microRNA-7 inhibits H4K20 monomethylation and suppresses epithelial-mesenchymal transition and the invasive potential of breast cancer cells. We showed that microRNA-7 promotes spontaneous DNA damages and sensitizes cells to induced DNA damages. Our experiments provide a molecular mechanism for the regulation of SET8 and extend the biological function of microRNA-7 to DNA damage response, supporting the pursuit of microRNA-7 as a potential target for breast cancer intervention.


Asunto(s)
Neoplasias de la Mama/metabolismo , Daño del ADN , N-Metiltransferasa de Histona-Lisina/metabolismo , MicroARNs/metabolismo , Proteínas de Neoplasias/metabolismo , ARN Neoplásico/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/prevención & control , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Femenino , N-Metiltransferasa de Histona-Lisina/genética , Histonas/genética , Histonas/metabolismo , Humanos , Metilación , MicroARNs/genética , Invasividad Neoplásica , Proteínas de Neoplasias/genética , ARN Neoplásico/genética
20.
J Biol Chem ; 288(25): 18271-82, 2013 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-23653357

RESUMEN

Faithful repair of DNA double-strand breaks is vital to the maintenance of genome integrity and proper cell functions. Histone modifications, such as reversible acetylation, phosphorylation, methylation, and ubiquitination, which collectively contribute to the establishment of distinct chromatin states, play important roles in the recruitment of repair factors to the sites of double-strand breaks. Here we report that histone acetyltransferase 1 (HAT1), a classical B type histone acetyltransferase responsible for acetylating the N-terminal tail of newly synthesized histone H4 in the cytoplasm, is a key regulator of DNA repair by homologous recombination in the nucleus. We found that HAT1 is required for the incorporation of H4K5/K12-acetylated H3.3 at sites of double-strand breaks through its HIRA-dependent histone turnover activity. Incorporated histones with specific chemical modifications facilitate subsequent recruitment of RAD51, a key repair factor in mammalian cells, to promote efficient homologous recombination. Significantly, depletion of HAT1 sensitized cells to DNA damage compromised the global chromatin structure, inhibited cell proliferation, and induced cell apoptosis. Our experiments uncovered a role for HAT1 in DNA repair in higher eukaryotic organisms and provide a mechanistic insight into the regulation of histone dynamics by HAT1.


Asunto(s)
Reparación del ADN , Histona Acetiltransferasas/metabolismo , Histonas/metabolismo , Ácido Anhídrido Hidrolasas , Secuencia de Aminoácidos , Western Blotting , Línea Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Células HCT116 , Células HEK293 , Células HeLa , Histona Acetiltransferasas/genética , Recombinación Homóloga , Humanos , Células MCF-7 , Microscopía Confocal , Datos de Secuencia Molecular , Unión Proteica , Interferencia de ARN , Recombinasa Rad51/metabolismo
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