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1.
J Hematol Oncol ; 17(1): 73, 2024 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-39183320

RESUMEN

Multiple classes of therapies targeting claudin-18 isoform 2 (CLDN18.2) are under development for the treatment of advanced gastroesophageal adenocarcinoma and other solid tumors. At the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, the final results of the phase 3 SPOTLIGHT trial were presented, demonstrating a significant survival benefit from the addition of the CLDN18.2-specific antibody zolbetuximab to chemotherapy in the first-line treatment of advanced gastroesophageal adenocarcinomas with ≥ 75% CLDN18.2 expression. Early-phase trial results presented at ASCO 2024 showed promising efficacy and safety of the afucosylated CLDN18.2-specific antibody FG-M108 in combination with chemotherapy in the first-line treatment of CLDN18.2-positive advanced gastroesophageal and pancreatic cancers. In addition, several early-phase trials presented at ASCO 2024 investigate other CLDN18.2-targeting approaches in CLDN18.2-positive refractory advanced solid tumors, including the CLDN18.2-targeting antibody-drug conjugates LM-302 and IBI343, the bispecific anti-CLDN18.2/CD3 antibody IBI38, and the chimeric antigen receptor T cell therapy satricabtagene autoleucel. These novel approaches could potentially expand the benefit of CLDN18.2-targeting therapies to a broader range of tumor types and to tumors expressing lower levels of CLDN18.2.


Asunto(s)
Claudinas , Humanos , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia
2.
Science ; 384(6702): eadh5548, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38900896

RESUMEN

The molecular mechanisms that regulate breast cancer cell (BCC) metastasis and proliferation within the leptomeninges (LM) are poorly understood, which limits the development of effective therapies. In this work, we show that BCCs in mice can invade the LM by abluminal migration along blood vessels that connect vertebral or calvarial bone marrow and meninges, bypassing the blood-brain barrier. This process is dependent on BCC engagement with vascular basement membrane laminin through expression of the neuronal pathfinding molecule integrin α6. Once in the LM, BCCs colocalize with perivascular meningeal macrophages and induce their expression of the prosurvival neurotrophin glial-derived neurotrophic factor (GDNF). Intrathecal GDNF blockade, macrophage-specific GDNF ablation, or deletion of the GDNF receptor neural cell adhesion molecule (NCAM) from BCCs inhibits breast cancer growth within the LM. These data suggest integrin α6 and the GDNF signaling axis as new therapeutic targets against breast cancer LM metastasis.


Asunto(s)
Neoplasias Óseas , Neoplasias de la Mama , Integrina alfa6 , Neoplasias Meníngeas , Meninges , Vías Nerviosas , Animales , Femenino , Humanos , Ratones , Membrana Basal/metabolismo , Neoplasias Óseas/secundario , Neoplasias Óseas/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Línea Celular Tumoral , Movimiento Celular , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Integrina alfa6/metabolismo , Laminina/metabolismo , Macrófagos/metabolismo , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/secundario , Meninges/patología , Invasividad Neoplásica , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Moléculas de Adhesión de Célula Nerviosa/genética , Transducción de Señal , Vías Nerviosas/metabolismo , Ratones SCID , Ratones Noqueados
3.
JTO Clin Res Rep ; 5(5): 100670, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38746048

RESUMEN

Introduction: The KRAS G12C inhibitor sotorasib was approved for treating advanced NSCLC in the second line or later on the basis of the CodeBreaK100 trial. Nevertheless, data on the real-world efficacy and safety of sotorasib, and to its optimal dose, remain limited. Methods: Patients treated with sotorasib for NSCLC through the Veterans Health Administration were retrospectively identified from the Corporate Data Warehouse. Survival, response, and toxicity data were obtained from chart review. Results: Among the 128 patients treated with sotorasib through the Veterans Health Administration, objective response rate was 34%, progression-free survival (PFS) six months, and overall survival 12 months. Similar PFS was observed among the 16 patients who received frontline sotorasib without any prior systemic therapy for NSCLC. Toxicity leading to sotorasib interruption or dose reduction occurred in 37% of patients, whereas sotorasib discontinuation for toxicity occurred in 25%. Notably, sotorasib dose reduction was associated with substantially improved PFS and OS. Conclusions: In this real-world study, the observed efficacy of sotorasib was similar to the results of CodeBreaK100. Patients who received frontline sotorasib had similar PFS to our overall cohort, suggesting that first-line sotorasib monotherapy may benefit patients who are not eligible for chemotherapy. Toxicities leading to sotorasib interruption, dose reduction, or discontinuation were common. Sotorasib dose reduction was associated with improved survival, suggesting that sotorasib dose reduction may not compromise efficacy.

4.
RNA ; 30(5): 570-582, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38531653

RESUMEN

RNA 2'-O-methylation (Nm) is highly abundant in noncoding RNAs including ribosomal RNA (rRNA), transfer RNA (tRNA), and small nuclear RNA (snRNA), and occurs in the 5' cap of virtually all messenger RNAs (mRNAs) in higher eukaryotes. More recently, Nm has also been reported to occur at internal sites in mRNA. High-throughput methods have been developed for the transcriptome-wide detection of Nm. However, these methods have mostly been applied to abundant RNAs such as rRNA, and the validity of the internal mRNA Nm sites detected with these approaches remains controversial. Nonetheless, Nm in both coding and noncoding RNAs has been demonstrated to impact cellular processes, including translation and splicing. In addition, Nm modifications at the 5' cap and possibly at internal sites in mRNA serve to prevent the binding of nucleic acid sensors, thus preventing the activation of the innate immune response by self-mRNAs. Finally, Nm has been implicated in a variety of diseases including cancer, cardiovascular diseases, and neurologic syndromes. In this review, we discuss current challenges in determining the distribution, regulation, function, and disease relevance of Nm, as well as potential future directions for the field.


Asunto(s)
ARN de Transferencia , ARN , ARN/genética , ARN/metabolismo , Metilación , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN de Transferencia/genética , ARN no Traducido/genética , ARN no Traducido/metabolismo , ARN Nuclear Pequeño/metabolismo , ARN Ribosómico/metabolismo
5.
J Gastrointest Cancer ; 55(2): 483-496, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38133871

RESUMEN

BACKGROUND: Gastroesophageal cancer is a major cause of cancer-related mortality worldwide. Treatment of both early stage and advanced disease remains highly reliant on cytotoxic chemotherapy. About 4-24% of gastroesophageal cancers are microsatellite instability high (MSI-H). The MSI-H subtype is associated with favorable prognosis, resistance to cytotoxic chemotherapy, and sensitivity to immune checkpoint inhibitors (ICI). Recent studies have demonstrated promising activity of ICIs in the MSI-H subtype, resulting in fundamental changes in the management of MSI-H gastroesophageal adenocarcinoma. PURPOSE: In this review, we discuss the prevalence, characteristics, prognosis, and management of MSI-H gastroesophageal adenocarcinoma, with a focus on recent and ongoing studies that have changed the landscape of treatment for the MSI-H subtype. We also discuss current challenges in the management of resectable and advanced MSI-H gastroesophageal cancer, including the need for more accurate biomarkers of response to ICI therapy.


Asunto(s)
Adenocarcinoma , Neoplasias Esofágicas , Inestabilidad de Microsatélites , Neoplasias Gástricas , Humanos , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/terapia , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/tratamiento farmacológico , Pronóstico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Unión Esofagogástrica/patología , Biomarcadores de Tumor/genética
6.
JCO Precis Oncol ; 7: e2300176, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38039430

RESUMEN

PURPOSE: Immune checkpoint inhibitors (ICIs) are used for an increasing number of indications across various tumor types, as well as several tumor-agnostic indications in patients with advanced cancer. Although many patients benefit from ICI therapy, others do not, highlighting a need for better predictive biomarkers. Tumor mutational burden (TMB) reflects the global number of mutations within a tumor and has been widely explored as a predictive biomarker of ICI response. The current tumor type-agnostic US Food and Drug Administration approval of pembrolizumab for metastatic solid tumors defines high TMB (TMB-H) as ≥10 mut/Mb as measured by FoundationOne CDx. This fixed cutoff may not be the ideal value across all solid tumors. METHODS: We performed a retrospective analysis of the association of survival outcomes with TMB in patients treated with ICI for five major cancer types, using real-world data from the VA. Survival was measured from initiation of ICI, and Kaplan-Meier survival curves were compared by log-rank test. RESULTS: Overall survival (OS) was significantly longer for patients with TMB-H versus TMB low tumors in non-small-cell lung cancer (NSCLC; n = 1,593), head and neck (H&N) cancer (n = 222), and urothelial cancer (n = 332). OS was not significantly different based on TMB status in melanoma (n = 207) or esophageal/gastric cancer (n = 248). CONCLUSION: Consistent with previous studies, a predictive value of TMB ≥10 mut/Mb for ICI response was found in NSCLC and H&N, but not in esophageal/gastric cancer. Although inconclusive in the literature, significant association was found in urothelial cancer. The predictive value of TMB in melanoma was inconclusive. Our analysis does not support the use of a fixed threshold for TMB as a standalone predictive biomarker for ICI across all solid tumors.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias de Cabeza y Cuello , Neoplasias Pulmonares , Melanoma , Neoplasias Gástricas , Estados Unidos/epidemiología , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/genética , Neoplasias Gástricas/tratamiento farmacológico , Estudios Retrospectivos , Biomarcadores de Tumor/genética , Melanoma/tratamiento farmacológico , Melanoma/genética
7.
JCO Precis Oncol ; 7: e2300275, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37769222
8.
JCO Precis Oncol ; 7: e2200692, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36926986

RESUMEN

PURPOSE: Neurotrophic tyrosine receptor kinase 1-3 (NTRK1-3) gene fusions are found in a broad range of tumor types. Clinical trials demonstrated high response rates to tropomyosin receptor kinase (TRK) inhibitors in NTRK fusion-positive cancers, but few reports have described real-world experience with these targeted agents. We evaluated the prevalence of NTRK fusions and the outcomes with TRK inhibitor therapy in a real-world population of patients in the Veterans Health Administration. METHODS: Patients with NTRK fusions or rearrangements were identified from the Veterans Affairs (VA) National Precision Oncology Program (NPOP), and patients who were prescribed TRK inhibitors were identified from the Corporate Data Warehouse. Baseline data and clinical outcomes were obtained by retrospective review of medical records. RESULTS: A total of 33 patients with NTRK fusions or rearrangements were identified, including 25 patients comprising 0.12% of all patients with solid tumors sequenced through VA NPOP. Twelve patients with NTRK fusions or rearrangements were treated with TRK inhibitors, none of whom had objective responses. Eight patients experienced toxicities leading to drug interruption, dose reduction, or discontinuation. CONCLUSION: In this retrospective study of VA patients, NTRK fusions and rearrangements were less common than in previous studies, and objective responses to TRK inhibitors were not observed. Real-world experience with TRK inhibitors differs markedly from clinical trial findings, possibly due to differences in patient demographics, tumor types, and sequencing methods. Our findings highlight the need to study TRK inhibitors in the real-world setting and in populations underrepresented in clinical trials.


Asunto(s)
Neoplasias , Veteranos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Tropomiosina/uso terapéutico , Receptor trkA/genética , Estudios Retrospectivos , Medicina de Precisión
9.
Clin Cancer Res ; 26(24): 6453-6463, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-32820017

RESUMEN

PURPOSE: Intrapatient heterogeneity of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in gastroesophageal adenocarcinoma (GEA) could influence their roles as predictive biomarkers for response to immune checkpoint inhibitors (ICI). In this retrospective analysis, we evaluated the spatiotemporal heterogeneity and prognostic relevance of PD-L1 expression and TMB in GEA. EXPERIMENTAL DESIGN: A cohort of 211 patients with stage II-IV GEA was retrospectively reviewed for a total of 407 tumor samples with PD-L1 expression data and 319 tumor samples with TMB data. PD-L1 status was defined as positive if combined positive score (CPS) ≥1 using the 22C3 pharmDx assay. TMB levels were categorized as low, intermediate, or high (≤5, 5-15, or >15 mutations/Mb), or using a single threshold (<10 or ≥10 mutation/Mb), determined by next-generation sequencing using a targeted gene panel. RESULTS: Of 407 tumors, 56% were PD-L1 negative and 44% PD-L1 positive. Of 319 tumors, 50% were TMB-low, 45% TMB-intermediate, and 5% TMB-high; 86% had <10 and 14% ≥10 mutations/Mb. TMB level was significantly associated with MSI-status. PD-L1 expression and TMB exhibited marked spatial heterogeneity between baseline primary and metastatic tumors (61% and 69% concordance), and temporal heterogeneity between tumors before and after chemotherapy (57%-63% and 73%-75% concordance). PD-L1 expression and TMB were not significantly associated with overall survival. CONCLUSIONS: PD-L1 expression and TMB exhibit marked spatial and temporal heterogeneity in GEA. This heterogeneity should be considered when obtaining tumor samples for molecular testing and when deciding whether ICI therapy is appropriate.See related commentary by Klempner et al., p. 6401.


Asunto(s)
Adenocarcinoma/patología , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Neoplasias Gástricas/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/genética , Biomarcadores de Tumor/genética , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Unión Esofagogástrica/efectos de los fármacos , Unión Esofagogástrica/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Tasa de Supervivencia , Adulto Joven
10.
Mol Cell ; 76(1): 70-81.e9, 2019 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-31445886

RESUMEN

N6-methyladenosine (m6A) modification occurs co-transcriptionally and impacts pre-mRNA processing; however, the mechanism of co-transcriptional m6A-dependent alternative splicing regulation is still poorly understood. Heterogeneous nuclear ribonucleoprotein G (hnRNPG) is an m6A reader protein that binds RNA through RRM and Arg-Gly-Gly (RGG) motifs. Here, we show that hnRNPG directly binds to the phosphorylated carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII) using RGG motifs in its low-complexity region. Through interactions with the phosphorylated CTD and nascent RNA, hnRNPG associates co-transcriptionally with RNAPII and regulates alternative splicing transcriptome-wide. m6A near splice sites in nascent pre-mRNA modulates hnRNPG binding, which influences RNAPII occupancy patterns and promotes exon inclusion. Our results reveal an integrated mechanism of co-transcriptional m6A-mediated splicing regulation, in which an m6A reader protein uses RGG motifs to co-transcriptionally interact with both RNAPII and m6A-modified nascent pre-mRNA to modulate RNAPII occupancy and alternative splicing.


Asunto(s)
Adenosina/análogos & derivados , Empalme Alternativo , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Precursores del ARN/biosíntesis , ARN Mensajero/biosíntesis , Transcripción Genética , Adenosina/metabolismo , Secuencias de Aminoácidos , Sitios de Unión , Exones , Células HEK293 , Ribonucleoproteínas Nucleares Heterogéneas/química , Ribonucleoproteínas Nucleares Heterogéneas/genética , Humanos , Unión Proteica , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Precursores del ARN/genética , ARN Mensajero/genética , Relación Estructura-Actividad
11.
RNA ; 25(9): 1218-1225, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31227565

RESUMEN

Pseudouridine (Ψ) is the most abundant RNA modification in cellular RNA present in tRNA/rRNA/snRNA and also in mRNA and long noncoding RNA (lncRNA). Elucidation of Ψ function in mRNA/lncRNA requires mapping and quantitative assessment of its modification fraction at single-base resolution. The most widely used Ψ mapping method for mRNA/lncRNA relies on its reaction with N-Cyclohexyl-N'-(2-morpholinoethyl)carbodiimide (CMC), forming an adduct with the Ψ base in RNA that is detectable by reverse transcription (RT) stops. However, this method has not produced consistent Ψ maps in mRNAs; furthermore, available protocols do not lend confidence to the estimation of Ψ fraction at specific sites, which is a crucial parameter for investigating the biological relevance of mRNA modifications. Here we develop a quantitative RT-PCR based method that can detect and quantify the modification fraction of target Ψ sites in mRNA/lncRNA, termed CMC-RT and ligation assisted PCR analysis of Ψ modification (CLAP). The method still relies on RT stop at a CMC-Ψ site, but uses site-specific ligation and PCR to generate two distinct PCR products in the same sample, corresponding to the modified and unmodified site, that are visualized by gel electrophoresis. CLAP not only requires a small amount of cellular RNA to validate Ψ sites but also determines the Ψ fraction semiquantitatively at target sites in mRNA/lncRNA. We determined the Ψ status of four mRNA sites and one lncRNA site whose modification fractions range from 30% to 84% in three human cell lines. Our method enables precise mapping and assessment of Ψ modification levels in low abundance cellular RNAs.


Asunto(s)
Seudouridina/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Línea Celular , Línea Celular Tumoral , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , ARN Ribosómico/genética , ARN Nuclear Pequeño/genética , ARN de Transferencia/genética , Transcripción Reversa/genética
12.
RNA Biol ; 15(7): 892-900, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29683381

RESUMEN

The abundant RNA modification pseudouridine (Ψ) has been mapped transcriptome-wide by chemically modifying pseudouridines with carbodiimide and detecting the resulting reverse transcription stops in high-throughput sequencing. However, these methods have limited sensitivity and specificity, in part due to the use of reverse transcription stops. We sought to use mutations rather than just stops in sequencing data to identify pseudouridine sites. Here, we identify reverse transcription conditions that allow read-through of carbodiimide-modified pseudouridine (CMC-Ψ), and we show that pseudouridines in carbodiimide-treated human ribosomal RNA have context-dependent mutation and stop rates in high-throughput sequencing libraries prepared under these conditions. Furthermore, accounting for the context-dependence of mutation and stop rates can enhance the detection of pseudouridine sites. Similar approaches could contribute to the sequencing-based detection of many RNA modifications.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Seudouridina/química , Seudouridina/genética , Procesamiento Postranscripcional del ARN , ARN Ribosómico/química , ARN Ribosómico/genética , Aptámeros de Nucleótidos/síntesis química , Aptámeros de Nucleótidos/genética , Aptámeros de Nucleótidos/metabolismo , CME-Carbodiimida/análogos & derivados , ADN Complementario/genética , Células HEK293 , Humanos , Mutación , Seudouridina/metabolismo , ADN Polimerasa Dirigida por ARN/química , Transcripción Reversa , Alineación de Secuencia
13.
Nat Cell Biol ; 20(3): 230-232, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29476150
14.
Methods ; 126: 105-111, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28454774

RESUMEN

The reversible N6-methyladenosine (m6A) modification of eukaryotic messenger RNAs (mRNAs) is a widespread regulatory mechanism that impacts every step in the mRNA life cycle. The effect of m6A on mRNA fate depends on the binding of "m6A reader" proteins - RNA binding proteins that specifically bind to RNAs containing m6A. Here, we describe an RNA pull-down method that can be used to identify novel m6A reader proteins starting from a known m6A-modified site in cellular or viral RNA. We further describe how a combination of immunoprecipitation-based sequencing methods can be used to identify m6A-modified sites bound by an m6A reader protein on a transcriptome-wide level. The discovery of new m6A reader proteins and their m6A-modified targets would provide further insight into the mechanisms and functions of m6A in the cell.


Asunto(s)
Adenosina/análogos & derivados , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Adenosina/análisis , Adenosina/genética , Adenosina/metabolismo , Sitios de Unión/fisiología , Electroforesis en Gel de Poliacrilamida/métodos , Células HEK293 , Humanos , Unión Proteica/fisiología , Proteínas de Unión al ARN/análisis
15.
Nucleic Acids Res ; 45(10): 6051-6063, 2017 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-28334903

RESUMEN

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic messenger RNA (mRNA), and affects almost every stage of the mRNA life cycle. The YTH-domain proteins can specifically recognize m6A modification to control mRNA maturation, translation and decay. m6A can also alter RNA structures to affect RNA-protein interactions in cells. Here, we show that m6A increases the accessibility of its surrounding RNA sequence to bind heterogeneous nuclear ribonucleoprotein G (HNRNPG). Furthermore, HNRNPG binds m6A-methylated RNAs through its C-terminal low-complexity region, which self-assembles into large particles in vitro. The Arg-Gly-Gly repeats within the low-complexity region are required for binding to the RNA motif exposed by m6A methylation. We identified 13,191 m6A sites in the transcriptome that regulate RNA-HNRNPG interaction and thereby alter the expression and alternative splicing pattern of target mRNAs. Low-complexity regions are pervasive among mRNA binding proteins. Our results show that m6A-dependent RNA structural alterations can promote direct binding of m6A-modified RNAs to low-complexity regions in RNA binding proteins.


Asunto(s)
Adenosina/análogos & derivados , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Conformación de Ácido Nucleico , ARN/metabolismo , Adenosina/química , Empalme Alternativo , Secuencia Conservada , Técnicas de Silenciamiento del Gen , Células HEK293 , Células HeLa , Humanos , Metiltransferasas/antagonistas & inhibidores , Metiltransferasas/genética , Oligorribonucleótidos/síntesis química , Oligorribonucleótidos/química , Oligorribonucleótidos/metabolismo , Filogenia , Unión Proteica , ARN/química , Interferencia de ARN , ARN Largo no Codificante/metabolismo , ARN Interferente Pequeño/genética , Análisis de Secuencia de ARN , Transcriptoma
16.
Mol Cell ; 63(2): 183-185, 2016 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-27447983

RESUMEN

In this issue of Molecular Cell, Wang et al. (2016a) report crystal structures of the core of the METTL3/METTL14 m(6)A methyltransferase complex and propose how the two subunits interact and cooperate to bind and methylate RNA.


Asunto(s)
Metiltransferasas/química , ARN/química
17.
J Mol Biol ; 428(5 Pt A): 822-833, 2016 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-26343757

RESUMEN

N(6)-Methyladenosine (m(6)A) is a reversible and abundant internal modification of messenger RNA (mRNA) and long noncoding RNA (lncRNA) with roles in RNA processing, transport, and stability. Although m(6)A does not preclude Watson-Crick base pairing, the N(6)-methyl group alters the stability of RNA secondary structure. Since changes in RNA structure can affect diverse cellular processes, the influence of m(6)A on mRNA and lncRNA structure has the potential to be an important mechanism for m(6)A function in the cell. Indeed, an m(6)A site in the lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was recently shown to induce a local change in structure that increases the accessibility of a U5-tract for recognition and binding by heterogeneous nuclear ribonucleoprotein C (HNRNPC). This m(6)A-dependent regulation of protein binding through a change in RNA structure, termed "m(6)A-switch", affects transcriptome-wide mRNA abundance and alternative splicing. To further characterize this first example of an m(6)A-switch in a cellular RNA, we used nuclear magnetic resonance and Förster resonance energy transfer to demonstrate the effect of m(6)A on a 32-nucleotide RNA hairpin derived from the m(6)A-switch in MALAT1. The observed imino proton nuclear magnetic resonance resonances and Förster resonance energy transfer efficiencies suggest that m(6)A selectively destabilizes the portion of the hairpin stem where the U5-tract is located, increasing the solvent accessibility of the neighboring bases while maintaining the overall hairpin structure. The m(6)A-modified hairpin has a predisposed conformation that resembles the hairpin conformation in the RNA-HNRNPC complex more closely than the unmodified hairpin. The m(6)A-induced structural changes in the MALAT1 hairpin can serve as a model for a large family of m(6)A-switches that mediate the influence of m(6)A on cellular processes.


Asunto(s)
Adenosina/análogos & derivados , Conformación de Ácido Nucleico , Unión Proteica , ARN Largo no Codificante/química , ARN Mensajero/química , Adenosina/química , Empalme Alternativo , Humanos , Modelos Moleculares
18.
Aging (Albany NY) ; 3(8): 733-53, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21937765

RESUMEN

It has long been understood that many of the same manipulations that increase longevity in Caenorhabditis elegans also increase resistance to various acute stressors, and vice-versa; moreover these findings hold in more complex organisms as well. Nevertheless, the mechanistic relationship between these phenotypes remains unclear, and in many cases the overlap between stress resistance and longevity is inexact. Here we review the known connections between stress resistance and longevity, discuss instances in which these connections are absent, and summarize the theoretical explanations that have been posited for these phenomena.


Asunto(s)
Caenorhabditis elegans/fisiología , Longevidad/fisiología , Estrés Fisiológico/fisiología , Animales , Regulación de la Expresión Génica , Calor
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