RESUMO
ATP, NAD+, and nucleic acids are abundant purines that, in addition to having critical intracellular functions, have evolved extracellular roles as danger signals released in response to cell lysis, apoptosis, degranulation, or membrane pore formation. In general ATP and NAD+ have excitatory and adenosine has anti-inflammatory effects on immune cells. This review focuses on recent advances in our understanding of purine release mechanisms, ectoenzymes that metabolize purines (CD38, CD39, CD73, ENPP1, and ENPP2/autotaxin), and signaling by key P2 purinergic receptors (P2X7, P2Y2, and P2Y12). In addition to metabolizing ATP or NAD+, some purinergic ectoenzymes metabolize other inflammatory modulators, notably lysophosphatidic acid and cyclic GMP-AMP (cGAMP). Also discussed are extracellular signaling effects of NAD+ mediated by ADP-ribosylation, and epigenetic effects of intracellular adenosine mediated by modification of S-adenosylmethionine-dependent DNA methylation.
Assuntos
Inflamação/imunologia , Purinas/metabolismo , Receptores Purinérgicos/metabolismo , ADP-Ribosilação , Trifosfato de Adenosina/metabolismo , Animais , Metilação de DNA , Humanos , Inflamação/genética , Inflamação/metabolismo , Lisofosfolipídeos/metabolismo , Transdução de SinaisRESUMO
Certain cancer types afflict female and male patients disproportionately. The reasons include differences in male/female physiology, effect of sex hormones, risk behavior, environmental exposures, and genetics of the sex chromosomes X and Y. Loss of Y (LOY) is common in peripheral blood cells in aging men, and this phenomenon is associated with several diseases. However, the frequency and role of LOY in tumors is little understood. Here, we present a comprehensive catalog of LOY in >5,000 primary tumors from male patients in the TCGA. We show that LOY rates vary by tumor type and provide evidence for LOY being either a passenger or driver event depending on context. LOY in uveal melanoma specifically is associated with age and survival and is an independent predictor of poor outcome. LOY creates common dependencies on DDX3X and EIF1AX in male cell lines, suggesting that LOY generates unique vulnerabilities that could be therapeutically exploited.
RESUMO
The 501Y.V2 variants of SARS-CoV-2 containing multiple mutations in spike are now dominant in South Africa and are rapidly spreading to other countries. Here, experiments with 18 pseudotyped viruses showed that the 501Y.V2 variants do not confer increased infectivity in multiple cell types except for murine ACE2-overexpressing cells, where a substantial increase in infectivity was observed. Notably, the susceptibility of the 501Y.V2 variants to 12 of 17 neutralizing monoclonal antibodies was substantially diminished, and the neutralization ability of the sera from convalescent patients and immunized mice was also reduced for these variants. The neutralization resistance was mainly caused by E484K and N501Y mutations in the receptor-binding domain of spike. The enhanced infectivity in murine ACE2-overexpressing cells suggests the possibility of spillover of the 501Y.V2 variants to mice. Moreover, the neutralization resistance we detected for the 501Y.V2 variants suggests the potential for compromised efficacy of monoclonal antibodies and vaccines.
Assuntos
COVID-19/imunologia , COVID-19/virologia , Evasão da Resposta Imune , SARS-CoV-2/patogenicidade , Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Antígenos Virais/imunologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Mutação/genética , SARS-CoV-2/genéticaRESUMO
The highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the United Kingdom, has gained a foothold across the world. Using S gene target failure (SGTF) and SARS-CoV-2 genomic sequencing, we investigated the prevalence and dynamics of this variant in the United States (US), tracking it back to its early emergence. We found that, while the fraction of B.1.1.7 varied by state, the variant increased at a logistic rate with a roughly weekly doubling rate and an increased transmission of 40%-50%. We revealed several independent introductions of B.1.1.7 into the US as early as late November 2020, with community transmission spreading it to most states within months. We show that the US is on a similar trajectory as other countries where B.1.1.7 became dominant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.
Assuntos
COVID-19 , Modelos Biológicos , SARS-CoV-2 , COVID-19/genética , COVID-19/mortalidade , COVID-19/transmissão , Feminino , Humanos , Masculino , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Estados Unidos/epidemiologiaRESUMO
Female Aedes aegypti mosquitoes bite humans to obtain blood to develop their eggs. Remarkably, their strong attraction to humans is suppressed for days after the blood meal by an unknown mechanism. We investigated a role for neuropeptide Y (NPY)-related signaling in long-term behavioral suppression and discovered that drugs targeting human NPY receptors modulate mosquito host-seeking. In a screen of all 49 predicted Ae. aegypti peptide receptors, we identified NPY-like receptor 7 (NPYLR7) as the sole target of these drugs. To obtain small-molecule agonists selective for NPYLR7, we performed a high-throughput cell-based assay of 265,211 compounds and isolated six highly selective NPYLR7 agonists that inhibit mosquito attraction to humans. NPYLR7 CRISPR-Cas9 null mutants are defective in behavioral suppression and resistant to these drugs. Finally, we show that these drugs can inhibit biting and blood-feeding on a live host, suggesting a novel approach to control infectious disease transmission by controlling mosquito behavior. VIDEO ABSTRACT.
Assuntos
Comportamento de Busca por Hospedeiro/efeitos dos fármacos , Mosquitos Vetores/efeitos dos fármacos , Receptores de Neuropeptídeo Y/agonistas , Aedes/metabolismo , Animais , Comportamento Alimentar/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Mordeduras e Picadas de Insetos , Receptores de Neuropeptídeo Y/metabolismo , Bibliotecas de Moléculas Pequenas/análiseRESUMO
The number of DNA polymerases identified in each organism has mushroomed in the past two decades. Most newly found DNA polymerases specialize in translesion synthesis and DNA repair instead of replication. Although intrinsic error rates are higher for translesion and repair polymerases than for replicative polymerases, the specialized polymerases increase genome stability and reduce tumorigenesis. Reflecting the numerous types of DNA lesions and variations of broken DNA ends, translesion and repair polymerases differ in structure, mechanism, and function. Here, we review the unique and general features of polymerases specialized in lesion bypass, as well as in gap-filling and end-joining synthesis.
Assuntos
Dano ao DNA , Enzimas Reparadoras do DNA/química , Enzimas Reparadoras do DNA/metabolismo , Reparo do DNA , DNA Polimerase Dirigida por DNA/química , DNA Polimerase Dirigida por DNA/metabolismo , Enzimas Reparadoras do DNA/classificação , DNA Polimerase Dirigida por DNA/classificação , Humanos , Modelos Biológicos , Modelos MolecularesRESUMO
Hypertension is usually accompanied by elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not clear. Recent advances revealed that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels and found that microglia in the hypothalamic paraventricular nucleus (PVN), a sympathetic center, were early responders to hypertensive challenges. Vasculature analyses revealed that the PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology relative to other brain regions. As such, the PVN was susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. Mechanistically, ATP ligation to microglial P2Y12 receptor was responsible for microglial inflammatory activation and the eventual sympathetic overflow. Together, these findings identified a distinct vasculature pattern rendering vulnerability of PVN pre-sympathetic neurons to hypertension-associated microglia-mediated inflammatory insults.
RESUMO
Hunger and pain are two competing signals that individuals must resolve to ensure survival. However, the neural processes that prioritize conflicting survival needs are poorly understood. We discovered that hunger attenuates behavioral responses and affective properties of inflammatory pain without altering acute nociceptive responses. This effect is centrally controlled, as activity in hunger-sensitive agouti-related protein (AgRP)-expressing neurons abrogates inflammatory pain. Systematic analysis of AgRP projection subpopulations revealed that the neural processing of hunger and inflammatory pain converge in the hindbrain parabrachial nucleus (PBN). Strikingly, activity in AgRP â PBN neurons blocked the behavioral response to inflammatory pain as effectively as hunger or analgesics. The anti-nociceptive effect of hunger is mediated by neuropeptide Y (NPY) signaling in the PBN. By investigating the intersection between hunger and pain, we have identified a neural circuit that mediates competing survival needs and uncovered NPY Y1 receptor signaling in the PBN as a target for pain suppression.
Assuntos
Neurônios/metabolismo , Dor/patologia , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Analgésicos Opioides/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Dieta , Comportamento Alimentar/efeitos dos fármacos , Formaldeído/toxicidade , Glutamato Descarboxilase/metabolismo , Locomoção/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Neurônios/efeitos dos fármacos , Dor/etiologia , Dor/metabolismo , Núcleos Parabraquiais/efeitos dos fármacos , Núcleos Parabraquiais/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Transdução de SinaisRESUMO
Purified translesion synthesis (TLS) DNA polymerases (Pols) replicate through DNA lesions with a low fidelity; however, TLS operates in a predominantly error-free manner in normal human cells. To explain this incongruity, here we determine whether Y family Pols, which play an eminent role in replication through a diversity of DNA lesions, are incorporated into a multiprotein ensemble and whether the intrinsically high error rate of the TLS Pol is ameliorated by the components in the ensemble. To this end, we provide evidence for an indispensable role of Werner syndrome protein (WRN) and WRN-interacting protein 1 (WRNIP1) in Rev1-dependent TLS by Y family Polη, Polι, or Polκ and show that WRN, WRNIP1, and Rev1 assemble together with Y family Pols in response to DNA damage. Importantly, we identify a crucial role of WRN's 3' â 5' exonuclease activity in imparting high fidelity on TLS by Y family Pols in human cells, as the Y family Pols that accomplish TLS in an error-free manner manifest high mutagenicity in the absence of WRN's exonuclease function. Thus, by enforcing high fidelity on TLS Pols, TLS mechanisms have been adapted to safeguard against genome instability and tumorigenesis.
Assuntos
DNA Polimerase Dirigida por DNA , Síntese de DNA Translesão , Helicase da Síndrome de Werner , Humanos , Dano ao DNA , Reparo do DNA , Replicação do DNA , DNA Polimerase Dirigida por DNA/metabolismo , Exonucleases/metabolismo , Síntese de DNA Translesão/genética , Helicase da Síndrome de Werner/genética , Helicase da Síndrome de Werner/metabolismoRESUMO
Human mixed-lineage leukemia (MLL) family methyltransferases methylate histone H3 lysine 4 to different methylation states (me1/me2/me3) with distinct functional outputs, but the mechanism underlying the different product specificities of MLL proteins remains unclear. Here, we develop methodologies to quantitatively measure the methylation rate difference between mono-, di-, and tri-methylation steps and demonstrate that MLL proteins possess distinct product specificities in the context of the minimum MLL-RBBP5-ASH2L complex. Comparative structural analyses of MLL complexes by X-ray crystal structures, fluorine-19 nuclear magnetic resonance, and molecular dynamics simulations reveal that the dynamics of two conserved tyrosine residues at the "F/Y (phenylalanine/tyrosine) switch" positions fine-tune the product specificity. The variation in the intramolecular interaction between SET-N and SET-C affects the F/Y switch dynamics, thus determining the product specificities of MLL proteins. These results indicate a modified F/Y switch rule applicable for most SET domain methyltransferases and implicate the functional divergence of MLL proteins.
Assuntos
Histona-Lisina N-Metiltransferase , Leucemia , Humanos , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Lisina/metabolismo , Flúor/metabolismo , Proteína de Leucina Linfoide-Mieloide/metabolismo , Tirosina , FenilalaninaRESUMO
Sex differences are pervasive in human health and disease. One major key to sex-biased differences lies in the sex chromosomes. Although the functions of the X chromosome proteins are well appreciated, how they compare with their Y chromosome homologs remains elusive. Herein, using ensemble and single-molecule techniques, we report that the sex chromosome-encoded RNA helicases DDX3X and DDX3Y are distinct in their propensities for liquid-liquid phase separation (LLPS), dissolution, and translation repression. We demonstrate that the N-terminal intrinsically disordered region of DDX3Y more strongly promotes LLPS than the corresponding region of DDX3X and that the weaker ATPase activity of DDX3Y, compared with DDX3X, contributes to the slower disassembly dynamics of DDX3Y-positive condensates. Interestingly, DDX3Y-dependent LLPS represses mRNA translation and enhances aggregation of FUS more strongly than DDX3X-dependent LLPS. Our study provides a platform for future comparisons of sex chromosome-encoded protein homologs, providing insights into sex differences in RNA metabolism and human disease.
Assuntos
RNA Helicases DEAD-box , RNA Helicases , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Feminino , Humanos , Masculino , Antígenos de Histocompatibilidade Menor/metabolismo , Biossíntese de Proteínas , Proteínas/metabolismo , RNA/metabolismo , RNA Helicases/genética , RNA Helicases/metabolismoRESUMO
Small noncoding piRNAs act as sequence-specific guides to repress complementary targets in Metazoa. Prior studies in Drosophila ovaries have demonstrated the function of the piRNA pathway in transposon silencing and therefore genome defense. However, the ability of the piRNA program to respond to different transposon landscapes and the role of piRNAs in regulating host gene expression remain poorly understood. Here, we comprehensively analyzed piRNA expression and defined the repertoire of their targets in Drosophila melanogaster testes. Comparison of piRNA programs between sexes revealed sexual dimorphism in piRNA programs that parallel sex-specific transposon expression. Using a novel bioinformatic pipeline, we identified new piRNA clusters and established complex satellites as dual-strand piRNA clusters. While sharing most piRNA clusters, the two sexes employ them differentially to combat the sex-specific transposon landscape. We found two piRNA clusters that produce piRNAs antisense to four host genes in testis, including CG12717/pirate, a SUMO protease gene. piRNAs encoded on the Y chromosome silence pirate, but not its paralog, to exert sex- and paralog-specific gene regulation. Interestingly, pirate is targeted by endogenous siRNAs in a sibling species, Drosophila mauritiana, suggesting distinct but related silencing strategies invented in recent evolution to regulate a conserved protein-coding gene.
Assuntos
Adaptação Fisiológica/genética , Elementos de DNA Transponíveis/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Células Germinativas/metabolismo , RNA Interferente Pequeno/metabolismo , Animais , Feminino , Masculino , Caracteres Sexuais , Fatores SexuaisRESUMO
Chemotherapy with cisplatin becomes limiting due to toxicity and secondary malignancies. In principle, therapeutics could be improved by targeting translesion synthesis (TLS) polymerases (Pols) that promote replication through intrastrand cross-links, the major cisplatin-induced DNA adduct. However, to specifically target malignancies with minimal adverse effects on normal cells, a good understanding of TLS mechanisms in normal versus cancer cells is paramount. We show that in normal cells, TLS through cisplatin intrastrand cross-links is promoted by Polη- or Polι-dependent pathways, both of which require Rev1 as a scaffolding component. In contrast, cancer cells require Rev1-Polζ. Our findings that a recently identified Rev1 inhibitor, JH-RE-06, purported to specifically disrupt Rev1 interaction with Polζ to block TLS through cisplatin adducts in cancer cells, abrogates Rev1's ability to function with Y family Pols as well, implying that by inactivating Rev1-dependent TLS in normal cells, this inhibitor will exacerbate the toxicity and tumorigenicity of chemotherapeutics with cisplatin.
Assuntos
Cisplatino , Dano ao DNA , Cisplatino/farmacologia , Reparo do DNA , Replicação do DNA , DNA Polimerase Dirigida por DNA/metabolismo , Proteínas Nucleares/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismoRESUMO
Until recently, cancer registries have only collected cancer clinical stage at diagnosis, before any therapy, and pathological stage after surgical resection, provided no treatment has been given before the surgery, but they have not collected stage data after neoadjuvant therapy (NAT). Because NAT is increasingly being used to treat a variety of tumors, it has become important to make the distinction between both the clinical and the pathological assessment without NAT and the assessment after NAT to avoid any misunderstanding of the significance of the clinical and pathological findings. It also is important that cancer registries collect data after NAT to assess response and effectiveness of this treatment approach on a population basis. The prefix y is used to denote stage after NAT. Currently, cancer registries of the American College of Surgeons' Commission on Cancer only partially collect y stage data, and data on the clinical response to NAT (yc or posttherapy clinical information) are not collected or recorded in a standardized fashion. In addition to NAT, nonoperative management after radiation and chemotherapy is being used with increasing frequency in rectal cancer and may be expanded to other treatment sites. Using examples from breast, rectal, and esophageal cancers, the pathological and imaging changes seen after NAT are reviewed to demonstrate appropriate staging.
Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias Esofágicas/diagnóstico , Terapia Neoadjuvante , Estadiamento de Neoplasias/métodos , Neoplasias Retais/diagnóstico , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Feminino , Humanos , Masculino , Estadiamento de Neoplasias/estatística & dados numéricos , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Sistema de Registros/estatística & dados numéricos , Resultado do Tratamento , Estados UnidosRESUMO
The promyelocytic leukemia (PML) body is a phase-separated nuclear structure physically associated with chromatin, implying its crucial roles in genome functions. However, its role in transcriptional regulation is largely unknown. We developed APEX-mediated chromatin labeling and purification (ALaP) to identify the genomic regions proximal to PML bodies. We found that PML bodies associate with active regulatory regions across the genome and with â¼300 kb of the short arm of the Y chromosome (YS300) in mouse embryonic stem cells. The PML body association with YS300 is essential for the transcriptional activity of the neighboring Y-linked clustered genes. Mechanistically, PML bodies provide specific nuclear spaces that the de novo DNA methyltransferase DNMT3A cannot access, resulting in the steady maintenance of a hypo-methylated state at Y-linked gene promoters. Our study underscores a new mechanism for gene regulation in the 3D nuclear space and provides insights into the functional properties of nuclear structures for genome function.
Assuntos
DNA (Citosina-5-)-Metiltransferases/metabolismo , Regulação da Expressão Gênica , Corpos de Inclusão Intranuclear/genética , Cromossomo Y/genética , Animais , Linhagem Celular , Cromatina/genética , Cromatina/metabolismo , RNA Helicases DEAD-box/genética , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA , DNA Metiltransferase 3A , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Células-Tronco Embrionárias/fisiologia , Endonucleases/genética , Sequenciamento de Nucleotídeos em Larga Escala , Corpos de Inclusão Intranuclear/metabolismo , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/genética , Enzimas Multifuncionais/genética , Família Multigênica , Estresse Oxidativo , Proteína da Leucemia Promielocítica/genética , Proteína da Leucemia Promielocítica/metabolismo , Proteínas/genética , Fatores de Transcrição/genética , Cromossomo Y/metabolismoRESUMO
Intestinal stem cells (ISCs) at the crypt base are responsible for the regeneration of the intestinal epithelium. However, how ISC self-renewal is regulated still remains unclear. Here we identified a circular RNA, circBtnl1, that is highly expressed in ISCs. Loss of circBtnl1 in mice enhanced ISC self-renewal capacity and epithelial regeneration, without changes in mRNA and protein levels of its parental gene Btnl1. Mechanistically, circBtnl1 and Atf4 mRNA competitively bound the ATP-dependent RNA helicase Ddx3y to impair the stability of Atf4 mRNA in wild-type ISCs. Furthermore, ATF4 activated Sox9 transcription by binding to its promoter via a unique motif, to enhance the self-renewal capacity and epithelial regeneration of ISCs. In contrast, circBtnl1 knockout promoted Atf4 mRNA stability and enhanced ATF4 expression, which caused Sox9 transcription to potentiate ISC stemness. These data indicate that circBtnl1-mediated Atf4 mRNA decay suppresses Sox9 transcription that negatively modulates self-renewal maintenance of ISCs.
Assuntos
Fator 4 Ativador da Transcrição , Mucosa Intestinal , Estabilidade de RNA , RNA Circular , RNA Mensageiro , Regeneração , Células-Tronco , Células-Tronco/citologia , Células-Tronco/fisiologia , Organoides/citologia , Camundongos Endogâmicos C57BL , Animais , Camundongos , RNA Circular/genética , RNA Circular/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/fisiologia , Regeneração/genética , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , RNA Mensageiro/metabolismo , Ativação Transcricional , Fatores de Transcrição SOX9/genética , Antígenos de Histocompatibilidade Menor/metabolismo , RNA Helicases DEAD-box/metabolismoRESUMO
Senescence and altered differentiation potential of bone marrow stromal cells (BMSCs) lead to age-related bone loss. As an important posttranscriptional regulatory pathway, alternative splicing (AS) regulates the diversity of gene expression and has been linked to induction of cellular senescence. However, the role of splicing factors in BMSCs during aging remains poorly defined. Herein, we found that the expression of the splicing factor Y-box binding protein 1 (YBX1) in BMSCs decreased with aging in mice and humans. YBX1 deficiency resulted in mis-splicing in genes linked to BMSC osteogenic differentiation and senescence, such as Fn1, Nrp2, Sirt2, Sp7, and Spp1, thus contributing to BMSC senescence and differentiation shift during aging. Deletion of Ybx1 in BMSCs accelerated bone loss in mice, while its overexpression stimulated bone formation. Finally, we identified a small compound, sciadopitysin, which attenuated the degradation of YBX1 and bone loss in old mice. Our study demonstrated that YBX1 governs cell fate of BMSCs via fine control of RNA splicing and provides a potential therapeutic target for age-related osteoporosis.
Assuntos
Células-Tronco Mesenquimais , Osteoporose , Humanos , Camundongos , Animais , Osteogênese/genética , Envelhecimento/metabolismo , Senescência Celular , Diferenciação Celular/genética , Osteoporose/metabolismo , Células da Medula Óssea , Proteína 1 de Ligação a Y-Box/metabolismoRESUMO
There is a growing body of research on the neural control of immunity and inflammation. However, it is not known whether the nervous system can regulate the production of inflammatory myeloid cells from hematopoietic progenitor cells in disease conditions. Myeloid cell numbers in diabetic patients were strongly correlated with plasma concentrations of norepinephrine, suggesting the role of sympathetic neuronal activation in myeloid cell production. The spleens of diabetic patients and mice contained higher numbers of tyrosine hydroxylase (TH)-expressing leukocytes that produced catecholamines. Granulocyte macrophage progenitors (GMPs) expressed the ß2 adrenergic receptor, a target of catecholamines. Ablation of splenic sympathetic neuronal signaling using surgical, chemical, and genetic approaches diminished GMP proliferation and myeloid cell development. Finally, mice lacking TH-producing leukocytes had reduced GMP proliferation, resulting in diminished myelopoiesis. Taken together, our study demonstrates that catecholamines produced by leukocytes and sympathetic nerve termini promote GMP proliferation and myeloid cell development.
Assuntos
Diabetes Mellitus/fisiopatologia , Células Progenitoras de Granulócitos e Macrófagos/citologia , Células Progenitoras de Granulócitos e Macrófagos/metabolismo , Mielopoese , Neuroimunomodulação , Sistema Nervoso Simpático/metabolismo , Antagonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus/sangue , Modelos Animais de Doenças , Feminino , Humanos , Leucócitos/enzimologia , Leucócitos/metabolismo , Masculino , Camundongos , Células Mieloides/citologia , Mielopoese/efeitos dos fármacos , Neuroimunomodulação/efeitos dos fármacos , Norepinefrina/sangue , Transdução de Sinais/efeitos dos fármacos , Baço/citologia , Baço/inervação , Baço/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
A significant fraction (â¼10%) of cancer cells maintain their telomere length via a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT). There are no known molecular, ALT-specific, therapeutic targets. We have identified TSPYL5 (testis-specific Y-encoded-like protein 5) as a PML body component, co-localizing with ALT telomeres and critical for ALT+ cell viability. TSPYL5 was described as an inhibitor of the USP7 deubiquitinase. We report that TSPYL5 prevents the poly-ubiquitination of POT1-a shelterin component-and protects POT1 from proteasomal degradation exclusively in ALT+ cells. USP7 depletion rescued POT1 poly-ubiquitination and loss, suggesting that the deubiquitinase activates POT1 E3 ubiquitin ligase(s). Similarly, PML depletion suppressed POT1 poly-ubiquitination, suggesting an interplay between USP7 and PML to trigger POT1 degradation in TSPYL5-depleted ALT+ cells. We demonstrate that ALT telomeres need to be protected from POT1 degradation in ALT-associated PML bodies and identify TSPYL5 as an ALT+ cancer-specific therapeutic target.
Assuntos
Neoplasias/genética , Proteínas Nucleares/genética , Homeostase do Telômero/genética , Proteínas de Ligação a Telômeros/genética , Peptidase 7 Específica de Ubiquitina/genética , Linhagem Celular , Sobrevivência Celular/genética , Humanos , Neoplasias/patologia , Proteína da Leucemia Promielocítica/genética , Ligação Proteica/genética , Proteólise , Complexo Shelterina , Telômero/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genéticaRESUMO
10 years ago, a detailed analysis showed that only 33% of genome-wide association study (GWAS) results included the X chromosome. Multiple recommendations were made to combat such exclusion. Here, we re-surveyed the research landscape to determine whether these earlier recommendations had been translated. Unfortunately, among the genome-wide summary statistics reported in 2021 in the NHGRI-EBI GWAS Catalog, only 25% provided results for the X chromosome and 3% for the Y chromosome, suggesting that the exclusion phenomenon not only persists but has also expanded into an exclusionary problem. Normalizing by physical length of the chromosome, the average number of studies published through November 2022 with genome-wide-significant findings on the X chromosome is â¼1 study/Mb. By contrast, it ranges from â¼6 to â¼16 studies/Mb for chromosomes 4 and 19, respectively. Compared with the autosomal growth rate of â¼0.086 studies/Mb/year over the last decade, studies of the X chromosome grew at less than one-seventh that rate, only â¼0.012 studies/Mb/year. Among the studies that reported significant associations on the X chromosome, we noted extreme heterogeneities in data analysis and reporting of results, suggesting the need for clear guidelines. Unsurprisingly, among the 430 scores sampled from the PolyGenic Score Catalog, 0% contained weights for sex chromosomal SNPs. To overcome the dearth of sex chromosome analyses, we provide five sets of recommendations and future directions. Finally, until the sex chromosomes are included in a whole-genome study, instead of GWASs, we propose such studies would more properly be referred to as "AWASs," meaning "autosome-wide scans."