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1.
Nat Commun ; 12(1): 4075, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210972

RESUMO

Long noncoding RNAs (lncRNAs) are known to regulate DNA damage response (DDR) and genome stability in proliferative cells. However, it remains unknown whether lncRNAs are involved in these vital biological processes in post-mitotic neurons. Here, we report and characterize a lncRNA, termed Brain Specific DNA-damage Related lncRNA1 (BS-DRL1), in the central nervous system. BS-DRL1 is a brain-specific lncRNA and depletion of BS-DRL1 in neurons leads to impaired DDR upon etoposide treatment in vitro. Mechanistically, BS-DRL1 interacts with HMGB1, a chromatin protein that is important for genome stability, and is essential for the assembly of HMGB1 on chromatin. BS-DRL1 mediated DDR exhibits cell-type specificity in the cortex and cerebellum in gamma-irradiated mice and BS-DRL1 knockout mice show impaired motor function and concomitant purkinje cell degeneration. Our study extends the understanding of lncRNAs in DDR and genome stability and implies a protective role of lncRNA against neurodegeneration.


Assuntos
Oxirredutases do Álcool/metabolismo , Dano ao DNA , Instabilidade Genômica , Proteína HMGB1/metabolismo , Neurônios/metabolismo , RNA Longo não Codificante/metabolismo , Oxirredutases do Álcool/genética , Animais , Fenômenos Biológicos , Cerebelo , Cromatina , Feminino , Regulação da Expressão Gênica , Proteína HMGB1/genética , Masculino , Camundongos , Camundongos Knockout , Mutação , RNA Longo não Codificante/genética
2.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204176

RESUMO

Age-related bone disorders such as osteoporosis or osteoarthritis are a major public health problem due to the functional disability for millions of people worldwide. Furthermore, fractures are associated with a higher degree of morbidity and mortality in the long term, which generates greater financial and health costs. As the world population becomes older, the incidence of this type of disease increases and this effect seems notably greater in those countries that present a more westernized lifestyle. Thus, increased efforts are directed toward reducing risks that need to focus not only on the prevention of bone diseases, but also on the treatment of persons already afflicted. Evidence is accumulating that dietary lipids play an important role in bone health which results relevant to develop effective interventions for prevent bone diseases or alterations, especially in the elderly segment of the population. This review focuses on evidence about the effects of dietary lipids on bone health and describes possible mechanisms to explain how lipids act on bone metabolism during aging. Little work, however, has been accomplished in humans, so this is a challenge for future research.


Assuntos
Envelhecimento/metabolismo , Osso e Ossos/metabolismo , Gorduras na Dieta/metabolismo , Animais , Autofagia/genética , Biomarcadores , Remodelação Óssea , Dieta , Instabilidade Genômica , Hormônios/metabolismo , Humanos , Osteíte/etiologia , Osteíte/metabolismo , Osteíte/patologia , Estresse Oxidativo
3.
Mol Cell ; 81(14): 2989-3006.e9, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34197737

RESUMO

Stalled DNA replication fork restart after stress as orchestrated by ATR kinase, BLM helicase, and structure-specific nucleases enables replication, cell survival, and genome stability. Here we unveil human exonuclease V (EXO5) as an ATR-regulated DNA structure-specific nuclease and BLM partner for replication fork restart. We find that elevated EXO5 in tumors correlates with increased mutation loads and poor patient survival, suggesting that EXO5 upregulation has oncogenic potential. Structural, mechanistic, and mutational analyses of EXO5 and EXO5-DNA complexes reveal a single-stranded DNA binding channel with an adjacent ATR phosphorylation motif (T88Q89) that regulates EXO5 nuclease activity and BLM binding identified by mass spectrometric analysis. EXO5 phospho-mimetic mutant rescues the restart defect from EXO5 depletion that decreases fork progression, DNA damage repair, and cell survival. EXO5 depletion furthermore rescues survival of FANCA-deficient cells and indicates EXO5 functions epistatically with SMARCAL1 and BLM. Thus, an EXO5 axis connects ATR and BLM in directing replication fork restart.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Replicação do DNA/genética , DNA/genética , Exonucleases/genética , Instabilidade Genômica/genética , RecQ Helicases/genética , Linhagem Celular , Linhagem Celular Tumoral , Dano ao DNA/genética , DNA Helicases/genética , Análise Mutacional de DNA/métodos , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Células HEK293 , Células HeLa , Humanos , Mutação/genética , Oncogenes/genética , Fosforilação/genética , Regulação para Cima/genética
4.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201700

RESUMO

DNA repair ensures genomic stability to achieve healthy ageing, including cognitive maintenance. Mutations on genes encoding key DNA repair proteins can lead to diseases with accelerated ageing phenotypes. Some of these diseases are xeroderma pigmentosum group A (XPA, caused by mutation of XPA), Cockayne syndrome group A and group B (CSA, CSB, and are caused by mutations of CSA and CSB, respectively), ataxia-telangiectasia (A-T, caused by mutation of ATM), and Werner syndrome (WS, with most cases caused by mutations in WRN). Except for WS, a common trait of the aforementioned progerias is neurodegeneration. Evidence from studies using animal models and patient tissues suggests that the associated DNA repair deficiencies lead to depletion of cellular nicotinamide adenine dinucleotide (NAD+), resulting in impaired mitophagy, accumulation of damaged mitochondria, metabolic derailment, energy deprivation, and finally leading to neuronal dysfunction and loss. Intriguingly, these features are also observed in Alzheimer's disease (AD), the most common type of dementia affecting more than 50 million individuals worldwide. Further studies on the mechanisms of the DNA repair deficient premature ageing diseases will help to unveil the mystery of ageing and may provide novel therapeutic strategies for AD.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/complicações , Dano ao DNA , Instabilidade Genômica , Doenças Neurodegenerativas/patologia , Animais , Reparo do DNA , Humanos , Mutação , Doenças Neurodegenerativas/etiologia
5.
Nat Commun ; 12(1): 3759, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145298

RESUMO

Pol µ is capable of performing gap-filling repair synthesis in the nonhomologous end joining (NHEJ) pathway. Together with DNA ligase, misincorporation of dGTP opposite the templating T by Pol µ results in a promutagenic T:G mispair, leading to genomic instability. Here, crystal structures and kinetics of Pol µ substituting dGTP for dATP on gapped DNA substrates containing templating T were determined and compared. Pol µ is highly mutagenic on a 2-nt gapped DNA substrate, with T:dGTP base pairing at the 3' end of the gap. Two residues (Lys438 and Gln441) interact with T:dGTP and fine tune the active site microenvironments. The in-crystal misincorporation reaction of Pol µ revealed an unexpected second dGTP in the active site, suggesting its potential mutagenic role among human X family polymerases in NHEJ.


Assuntos
Pareamento Incorreto de Bases/genética , Dano ao DNA/genética , Reparo do DNA por Junção de Extremidades/genética , DNA Polimerase Dirigida por DNA/metabolismo , Instabilidade Genômica/genética , Pareamento de Bases/genética , DNA/química , DNA Ligases/metabolismo , DNA Polimerase Dirigida por DNA/genética , Guanosina Trifosfato/química , Humanos
6.
Nat Commun ; 12(1): 3520, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112784

RESUMO

The Immunodeficiency Centromeric Instability Facial Anomalies (ICF) 4 syndrome is caused by mutations in LSH/HELLS, a chromatin remodeler promoting incorporation of histone variant macroH2A. Here, we demonstrate that LSH depletion results in degradation of nascent DNA at stalled replication forks and the generation of genomic instability. The protection of stalled forks is mediated by macroH2A, whose knockdown mimics LSH depletion and whose overexpression rescues nascent DNA degradation. LSH or macroH2A deficiency leads to an impairment of RAD51 loading, a factor that prevents MRE11 and EXO1 mediated nascent DNA degradation. The defect in RAD51 loading is linked to a disbalance of BRCA1 and 53BP1 accumulation at stalled forks. This is associated with perturbed histone modifications, including abnormal H4K20 methylation that is critical for BRCA1 enrichment and 53BP1 exclusion. Altogether, our results illuminate the mechanism underlying a human syndrome and reveal a critical role of LSH mediated chromatin remodeling in genomic stability.


Assuntos
DNA Helicases/metabolismo , Replicação do DNA , Instabilidade Genômica , Histonas/metabolismo , Rad51 Recombinase/metabolismo , Animais , Proteína BRCA1/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Montagem e Desmontagem da Cromatina/genética , Sequenciamento de Cromatina por Imunoprecipitação , DNA Helicases/deficiência , DNA Helicases/genética , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Replicação do DNA/genética , Epigênese Genética , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , Instabilidade Genômica/genética , Histonas/deficiência , Histonas/genética , Humanos , Proteína Homóloga a MRE11/genética , Proteína Homóloga a MRE11/metabolismo , Metilação , Camundongos , RNA Interferente Pequeno , Rad51 Recombinase/genética , Regulação para Cima
7.
Theranostics ; 11(15): 7175-7187, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158843

RESUMO

Background: Homologous recombination deficiency (HRD) is a common molecular characteristic of genomic instability, and has been proven to be a biomarker for target therapy. However, until now, no research has explored the changes in the transcriptomics landscape of HRD tumors. Methods: The HRD score was established from SNP array data of breast cancer patients from the cancer genome atlas (TCGA) database. The transcriptome data of patients with different HRD scores were analyzed to identify biomarkers associated with HRD. The candidate biomarkers were validated in the gene expression omnibus (GEO) database and immunotherapy cohorts. Results: Based on data from the gene expression profile and clinical characteristics from 1310 breast cancer patients, including TCGA database and GEO database, we found that downstream targets of the cGAS-STING pathway, such as CXCL10, were upregulated in HRD tumors and could be used as a predictor of survival outcome in triple-negative breast cancer (TNBC) patients. Further comprehensive analysis of the tumor immune microenvironment (TIME) revealed that the expression of CXCL10 was positively correlated with neoantigen load and infiltrating immune cells. Finally, in vivo experimental data and clinical trial data confirmed that the expression of CXCL10 could be used as a biomarker for anti-PD-1/PD-L1 therapy. Conclusions: Together, our study not only revealed that CXCL10 is associated with HRD but also introduced a potential new perspective for identifying prognostic biomarkers of immunotherapy.


Assuntos
Neoplasias da Mama , Quimiocina CXCL10 , Bases de Dados de Ácidos Nucleicos , Instabilidade Genômica/imunologia , Recombinação Homóloga , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Neoplasias/imunologia , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Feminino , Humanos , Imunoterapia , Proteínas de Neoplasias/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
8.
Nucleic Acids Res ; 49(12): 6832-6848, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34157114

RESUMO

Rad51 is the key protein in homologous recombination that plays important roles during DNA replication and repair. Auxiliary factors regulate Rad51 activity to facilitate productive recombination, and prevent inappropriate, untimely or excessive events, which could lead to genome instability. Previous genetic analyses identified a function for Rrp1 (a member of the Rad5/16-like group of SWI2/SNF2 translocases) in modulating Rad51 function, shared with the Rad51 mediator Swi5-Sfr1 and the Srs2 anti-recombinase. Here, we show that Rrp1 overproduction alleviates the toxicity associated with excessive Rad51 levels in a manner dependent on Rrp1 ATPase domain. Purified Rrp1 binds to DNA and has a DNA-dependent ATPase activity. Importantly, Rrp1 directly interacts with Rad51 and removes it from double-stranded DNA, confirming that Rrp1 is a translocase capable of modulating Rad51 function. Rrp1 affects Rad51 binding at centromeres. Additionally, we demonstrate in vivo and in vitro that Rrp1 possesses E3 ubiquitin ligase activity with Rad51 as a substrate, suggesting that Rrp1 regulates Rad51 in a multi-tiered fashion.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Rad51 Recombinase/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Adenosina Trifosfatases/metabolismo , DNA Fúngico/metabolismo , Proteínas de Ligação a DNA/isolamento & purificação , Proteínas de Ligação a DNA/fisiologia , Instabilidade Genômica , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/isolamento & purificação , Proteínas de Schizosaccharomyces pombe/fisiologia
9.
Nat Commun ; 12(1): 3937, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34168151

RESUMO

Although human nucleoporin Tpr is frequently deregulated in cancer, its roles are poorly understood. Here we show that Tpr depletion generates transcription-dependent replication stress, DNA breaks, and genomic instability. DNA fiber assays and electron microscopy visualization of replication intermediates show that Tpr deficient cells exhibit slow and asymmetric replication forks under replication stress. Tpr deficiency evokes enhanced levels of DNA-RNA hybrids. Additionally, complementary proteomic strategies identify a network of Tpr-interacting proteins mediating RNA processing, such as MATR3 and SUGP2, and functional experiments confirm that their depletion trigger cellular phenotypes shared with Tpr deficiency. Mechanistic studies reveal the interplay of Tpr with GANP, a component of the TREX-2 complex. The Tpr-GANP interaction is supported by their shared protein level alterations in a cohort of ovarian carcinomas. Our results reveal links between nucleoporins, DNA transcription and replication, and the existence of a network physically connecting replication forks with transcription, splicing, and mRNA export machinery.


Assuntos
Replicação do DNA , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Acetiltransferases/genética , Acetiltransferases/metabolismo , Sobrevivência Celular , Dano ao DNA , Instabilidade Genômica , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas/genética , Transporte de RNA
11.
Mutat Res ; 787: 108368, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083032

RESUMO

Redox homeostasis is imperative to maintain normal physiologic and metabolic functions. Radiotherapy disturbs this balance and induces genomic instability in diseased cells. However, radiation-induced effects propagate beyond the targeted cells, affecting the adjacent non-targeted cells (bystander effects). The cellular impact of radiation, thus, encompasses both targeted and non-targeted effects. Use of external modulators along with radiation can increase radio-therapeutic efficiency. The modulators' classification as protectors or sensitizers depends on interactions with damaged DNA molecules. Thus, it is necessary to realize the functions of various radio-sensitizers or radio-protectors in both irradiated and bystander cells. This review focuses on some modulators of radiation-induced bystander effects (RIBE) and their action mechanisms. Knowledge about the underlying signaling cross-talk may promote selective sensitization of radiation-targeted cells and protection of bystander cells.


Assuntos
Instabilidade Genômica/fisiologia , Animais , Efeito Espectador , Instabilidade Genômica/genética , Homeostase/genética , Homeostase/fisiologia , Humanos , Oxirredução , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
12.
Mutat Res ; 787: 108346, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083038

RESUMO

DNA replication stress is a major source of DNA damage, including double-stranded breaks that promote DNA damage response (DDR) signaling. Inefficient repair of such lesions can affect genome integrity. During DNA replication different factors act on chromatin remodeling in a coordinated way. While recent studies have highlighted individual molecular mechanisms of interaction, less is known about the orchestration of chromatin changes under replication stress. In this review we attempt to explore the complex relationship between DNA replication stress, DDR and genome integrity in mammalian cells, taking into account the role of chromatin disposition as an important modulator of DNA repair. Recent data on chromatin restoration and epigenetic re-establishment after DNA replication stress are reviewed.


Assuntos
Dano ao DNA/fisiologia , Replicação do DNA/fisiologia , Instabilidade Genômica/fisiologia , Animais , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina/genética , Montagem e Desmontagem da Cromatina/fisiologia , Dano ao DNA/genética , Replicação do DNA/genética , Instabilidade Genômica/genética , Humanos
13.
Mutat Res ; 787: 108370, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083045

RESUMO

Despite being an important diagnostic and treatment modality, ionizing radiation (IR) is also known to cause genotoxicity and multiple side effects leading to secondary carcinogenesis. While modern cancer radiation therapy has improved patient recovery and enhanced survival rates, the risk of radiation-related adverse effects has become a growing challenge. It is now well-accepted that IR-induced side effects are not exclusively restricted to exposed cells but also spread to distant 'bystander' cells and even to the unexposed progeny of the irradiated cells. These 'off-targeted' effects involve a plethora of molecular events depending on the type of radiation and tumor tissue background. While the mechanisms by which off-targeted effects arise remain obscure, emerging evidence based on the non-mendelian inheritance of various manifestations of them as well as their persistence for longer periods supports a contribution of epigenetic factors. This review focuses on the major epigenetic phenomena including DNA methylation, histone modifications, and small RNA mediated silencing and their versatile role in the manifestation of IR induced off-targeted effects. As short- and long-range communication vehicles respectively, the role of gap junctions and exosomes in spreading these epigenetic-alteration driven off-targeted effects is also discussed. Furthermore, this review emphasizes the possible therapeutic potentials of these epigenetic mechanisms and how beneficial outcomes could potentially be achieved by targeting various signaling molecules involved in these mechanisms.


Assuntos
Epigênese Genética/genética , Efeito Espectador/genética , Efeito Espectador/fisiologia , Metilação de DNA/genética , Metilação de DNA/fisiologia , Instabilidade Genômica/genética , Instabilidade Genômica/fisiologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo
14.
Mutat Res ; 787: 108359, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083047

RESUMO

Genome instability denotes an increased tendency to alterations in the genome during cell life cycle, driven by a large variety of endogenous and exogenous insults. Ageing is characterized by the presence of damage to various cellular constituents, but genome alterations, randomly accumulating with age in different tissues, constitute the key target in this process, and are believed to be the main factor of ageing. Age-related failure of DNA repair pathways allows DNA lesions to occur more frequently, and their accumulation over time contributes to the age-associated decrease in genome integrity in somatic cells. The micronucleus (MN) test is one of the most widely used assays to evaluate genomic instability in different surrogate tissues. A large number of studies has consistently shown a progressive increase in MN frequency with age, starting from very young age groups onwards. Therefore, MN frequency is a suitable biomarker of genomic instability in ageing. Frailty is a multidimensional geriatric syndrome of unsuccessful ageing, characterized by decreased biological reserves and increased vulnerability to external stressors, involving a higher risk of negative health outcomes. Although there is a well-founded belief that genome instability is involved in the frailty syndrome, only two studies investigated the relationship between MN frequency and frailty, not allowing to draw a definite conclusion on the utility of this biomarker for frailty detection. The use of MN and other genomic biomarkers in the detection and follow-up of patients affected by or at risk of frailty has the potential to accumulate evidence on the clinical impact of this approach in the identification and control of frailty in older people.


Assuntos
Instabilidade Genômica/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/fisiologia , Reparo do DNA/genética , Reparo do DNA/fisiologia , Feminino , Idoso Fragilizado , Humanos , Masculino , Testes para Micronúcleos/métodos
15.
Mutat Res ; 787: 108344, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083053

RESUMO

Respiratory tissues are highly susceptible to diseases due to the constant exposure to physical and chemical airborne pollutants. Chronic obstructive pulmonary disease (COPD) and lung cancer are among the most common causes of serious illness and death worldwide. The inflammatory environment associated with these respiratory diseases has long been accepted as the major player in the development of airway abnormalities. The presence and relevance of DNA damage and genomic instability makes the micronucleus assay a suitable candidate to quantitatively estimate these early pathogenetic events. A systematic review and meta-analysis were planned to determine underlying common mechanisms that can explain the relationships between COPD and lung cancer. A total of 17 studies from Jan 1999 to Dec 2019 comparing micronucleus frequency in patients affected by respiratory diseases vs healthy controls were analysed. Our results confirmed the presence of significant association between MN frequency and the diseases investigated, and suggested a circle of events linking inflammation induced oxidative stress to the risk of disease through genomic instability and hypoxia. Therefore, using non-invasive, robust and cost effective genomic instability assays such as the micronucleus assay, would allow us to capture unique phenotypic and biological changes that would allow the identification of subjects at high risk of developing lung diseases and improve early detection strategies.


Assuntos
Instabilidade Genômica/genética , Inflamação/genética , Neoplasias Pulmonares/genética , Testes para Micronúcleos/métodos , Doença Pulmonar Obstrutiva Crônica/genética , Animais , Humanos , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia
16.
Aging (Albany NY) ; 13(11): 15164-15192, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34081618

RESUMO

Long non-coding RNAs (lncRNAs) comprise an integral part of the eukaryotic transcriptome. Alongside proteins, lncRNAs modulate lncRNA-based gene signatures of unstable transcripts, play a crucial role as antisense lncRNAs to control intracellular homeostasis and are implicated in tumorigenesis. However, the role of genomic instability-associated lncRNAs in low-grade gliomas (LGG) has not been fully explored. In this study, lncRNAs expression and somatic mutation profiles in low-grade glioma genome were used to identify eight novel mutant-derived genomic instability-associated lncRNAs including H19, FLG-AS1, AC091932.1, AC064875.1, AL138767.3, AC010273.2, AC131097.4 and ISX-AS1. Patients from the LGG gene mutagenome atlas were grouped into training and validation sets to test the performance of the signature. The genomic instability-associated lncRNAs signature (GILncSig) was then validated using multiple external cohorts. A total of 59 novel genomic instability-associated lncRNAs in LGG were used for least absolute shrinkage and selection operator (Lasso), single and multifactor Cox regression analysis using the training set. Furthermore, the independent predictive role of risk features in the training and validation sets were evaluated through survival analysis, receiver operating feature analysis and construction of a nomogram. Patients with IDH1 mutation status were grouped into two different risk groups based on the GILncSig score. The low-risk group showed a relatively higher rate of IDH1 mutations compared with patients in the high-risk group. Furthermore, patients in the low-risk group had better prognosis compared with patients in the high-risk group. In summary, this study reports a reliable prognostic prediction signature and provides a basis for further investigation of the role of lncRNAs on genomic instability. In addition, lncRNAs in the signature can be used as new targets for treatment of LGG.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Perfilação da Expressão Gênica , Instabilidade Genômica , Glioma/genética , Glioma/patologia , RNA Longo não Codificante/genética , Adulto , Área Sob a Curva , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Isocitrato Desidrogenase/genética , Estimativa de Kaplan-Meier , Masculino , Análise Multivariada , Mutação/genética , Gradação de Tumores , Prognóstico , Modelos de Riscos Proporcionais , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Curva ROC , Reprodutibilidade dos Testes
17.
Nat Commun ; 12(1): 3856, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158470

RESUMO

The MRN complex (MRX in Saccharomyces cerevisiae, made of Mre11, Rad50 and Nbs1/Xrs2) initiates double-stranded DNA break repair and activates the Tel1/ATM kinase in the DNA damage response. Telomeres counter both outcomes at chromosome ends, partly by keeping MRN-ATM in check. We show that MRX is disabled by telomeric protein Rif2 through an N-terminal motif (MIN, MRN/X-inhibitory motif). MIN executes suppression of Tel1, DNA end-resection and non-homologous end joining by binding the Rad50 N-terminal region. Our data suggest that MIN promotes a transition within MRX that is not conductive for endonuclease activity, DNA-end tethering or Tel1 kinase activation, highlighting an Achilles' heel in MRN, which we propose is also exploited by the RIF2 paralog ORC4 (Origin Recognition Complex 4) in Kluyveromyces lactis and the Schizosaccharomyces pombe telomeric factor Taz1, which is evolutionarily unrelated to Orc4/Rif2. This raises the possibility that analogous mechanisms might be deployed in other eukaryotes as well.


Assuntos
Motivos de Aminoácidos , DNA Helicases/metabolismo , Endodesoxirribonucleases/metabolismo , Exodesoxirribonucleases/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Telômero/metabolismo , Sequência de Aminoácidos , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , DNA Helicases/genética , DNA Fúngico/genética , DNA Fúngico/metabolismo , Endodesoxirribonucleases/genética , Exodesoxirribonucleases/genética , Instabilidade Genômica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Complexo de Reconhecimento de Origem/genética , Complexo de Reconhecimento de Origem/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Homologia de Sequência de Aminoácidos , Telômero/genética , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo
18.
Nat Commun ; 12(1): 3887, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162889

RESUMO

ATRX is a tumor suppressor that has been associated with protection from DNA replication stress, purportedly through resolution of difficult-to-replicate G-quadruplex (G4) DNA structures. While several studies demonstrate that loss of ATRX sensitizes cells to chemical stabilizers of G4 structures, the molecular function of ATRX at G4 regions during replication remains unknown. Here, we demonstrate that ATRX associates with a number of the MCM replication complex subunits and that loss of ATRX leads to G4 structure accumulation at newly synthesized DNA. We show that both the helicase domain of ATRX and its H3.3 chaperone function are required to protect cells from G4-induced replicative stress. Furthermore, these activities are upstream of heterochromatin formation mediated by the histone methyltransferase, ESET, which is the critical molecular event that protects cells from G4-mediated stress. In support, tumors carrying mutations in either ATRX or ESET show increased mutation burden at G4-enriched DNA sequences. Overall, our study provides new insights into mechanisms by which ATRX promotes genome stability with important implications for understanding impacts of its loss on human disease.


Assuntos
Replicação do DNA/genética , DNA/genética , Quadruplex G , Heterocromatina/genética , Proteína Nuclear Ligada ao X/genética , Células Cultivadas , Sequenciamento de Cromatina por Imunoprecipitação/métodos , DNA/química , DNA/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Instabilidade Genômica/genética , Células HeLa , Histonas/genética , Histonas/metabolismo , Humanos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Mutação , Conformação de Ácido Nucleico , Proteína Nuclear Ligada ao X/metabolismo
19.
Anticancer Res ; 41(6): 2773-2779, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083267

RESUMO

Head and neck carcinoma (HNC) comprises a variety of pathological entities. Among them, squamous cell carcinoma (SCC) is histo-pathologically prominent. Specific malignancies, such as nasopharyngeal carcinoma (NPC) arise also from the same anatomical region. In all of them, genomic instability (GI) is implicated not only in the early stages of epithelial malignant transformation, but also in the aggressiveness of the corresponding phenotypes. Among the molecules that are frequently deregulated in solid malignancies including HNCs, topoisomerases (Topo) are of increased significance due to their involvement in DNA topological, structural, and functional stability. The main members are Topo I (20q11), Topo II alpha (17q21) and Topo IIb (3p24). In the current article, we describe the mechanisms of Topo I and Topo IIa deregulation leading to GI in a variety of HNCs. Furthermore, novel data regarding the corresponding targeted therapeutic strategies are presented.


Assuntos
DNA Topoisomerases Tipo I/metabolismo , Instabilidade Genômica , Neoplasias de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , DNA Topoisomerases Tipo I/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
20.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(5): 552-557, 2021 May 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34148893

RESUMO

Lymphoma is one of the most common malignant tumor of the hematologic system. The genome instability is not only an important molecular basis for the development of lymphoma, but also has important value in the diagnosis and prognosis of lymphoma. There are 2 types of genome instability: Microsatellite instability (MSI/MIN) at gene level and chromosomal instability at chromosome level. Through the study on genes associated with lymphoma, the unstable genes associated with lymphoma could be found, meanwhile the mechanism of its occurrence and development of lymphoma could be explored, and the important basis of molecular biology could also be provided in the field of current hot lymphoma precision medical research.


Assuntos
Linfoma , Neoplasias , Instabilidade Genômica , Humanos , Linfoma/genética , Instabilidade de Microssatélites , Repetições de Microssatélites
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