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1.
Adv Exp Med Biol ; 1167: 105-112, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31520351

RESUMO

Human P53 (HsP53) is the most frequently mutated gene associated with cancers. Despite heightened research interest over the last four decades, a clear picture of how wild type HsP53 functions as the guardian against malignant transformation remains elusive. Studying the ortholog of P53 in the genetic model organism Drosophila melanogaster (DmP53) has revealed many interesting insights. This chapter focuses on recent findings that have shed light on how DmP53 -mediated apoptosis plays an important role in maintaining genome integrity, and how the immediate output of activated DmP53 is determined by the epigenetic landscape of individual cells.


Assuntos
Apoptose , Proteínas de Drosophila/genética , Drosophila melanogaster , Proteína Supressora de Tumor p53/genética , Animais , Epigênese Genética , Instabilidade Genômica , Humanos
2.
BMC Plant Biol ; 19(1): 346, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391002

RESUMO

BACKGROUND: The safety assessment and control of stacked transgenic crops is increasingly important due to continuous crop development and is urgently needed in China. The genetic stability of foreign genes and unintended effects are the primary problems encountered in safety assessment. Omics techniques are useful for addressing these problems. The stacked transgenic maize variety 12-5 × IE034, which has insect-resistant and glyphosate-tolerant traits, was developed via a breeding stack using 12-5 and IE034 as parents. Using 12-5 × IE034, its parents (12-5 and IE034), and different maize varieties as materials, we performed proteomic profiling, molecular characterization and a genetic stability analysis. RESULTS: Our results showed that the copy number of foreign genes in 12-5 × IE034 is identical to that of its parents 12-5 and IE034. Foreign genes can be stably inherited over different generations. Proteomic profiling analysis found no newly expressed proteins in 12-5 × IE034, and the differences in protein expression between 12 and 5 × IE034 and its parents were within the range of variation of conventional maize varieties. The expression levels of key enzymes participating in the shikimic acid pathway which is related to glyphosate tolerance of 12-5 × IE034 were not significantly different from those of its parents or five conventional maize varieties, which indicated that without selective pressure by glyphosate, the introduced EPSPS synthase is not has a pronounced impact on the synthesis of aromatic amino acids in maize. CONCLUSIONS: Stacked-trait development via conventional breeding did not have an impact on the genetic stability of T-DNA, and the impact of stacked breeding on the maize proteome was less significant than that of genotypic differences. The results of this study provide a theoretical basis for the development of a safety assessment approach for stacked-trait transgenic crops in China.


Assuntos
Variação Genética , Melhoramento Vegetal , Plantas Geneticamente Modificadas , Zea mays/genética , China , Inocuidade dos Alimentos , Dosagem de Genes , Instabilidade Genômica , Análise de Perigos e Pontos Críticos de Controle , Proteômica
3.
Nature ; 571(7766): 521-527, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31270457

RESUMO

The integrity of genomes is constantly threatened by problems encountered by the replication fork. BRCA1, BRCA2 and a subset of Fanconi anaemia proteins protect stalled replication forks from degradation by nucleases, through pathways that involve RAD51. The contribution and regulation of BRCA1 in replication fork protection, and how this role relates to its role in homologous recombination, is unclear. Here we show that BRCA1 in complex with BARD1, and not the canonical BRCA1-PALB2 interaction, is required for fork protection. BRCA1-BARD1 is regulated by a conformational change mediated by the phosphorylation-directed prolyl isomerase PIN1. PIN1 activity enhances BRCA1-BARD1 interaction with RAD51, thereby increasing the presence of RAD51 at stalled replication structures. We identify genetic variants of BRCA1-BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1-BARD1 that are required for fork protection and associated with cancer development. Together, these findings reveal a BRCA1-mediated pathway that governs replication fork protection.


Assuntos
Proteína BRCA1/química , Proteína BRCA1/metabolismo , Replicação do DNA , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteína BRCA1/genética , Linhagem Celular Tumoral , Replicação do DNA/genética , Instabilidade Genômica/genética , Humanos , Isomerismo , Mutação , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Fosforilação , Fosfosserina/metabolismo , Ligação Proteica , Rad51 Recombinase/metabolismo
4.
Nat Commun ; 10(1): 3101, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308377

RESUMO

The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.


Assuntos
Adenocarcinoma/genética , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Esofágicas/genética , Perfilação da Expressão Gênica/métodos , Medicina de Precisão/métodos , Antineoplásicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Biologia Computacional/métodos , Conjuntos de Dados como Assunto , Progressão da Doença , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Instabilidade Genômica , Humanos , Aprendizado de Máquina , Modelos Genéticos , Família Multigênica/efeitos dos fármacos , Taxa de Mutação , Polimorfismo de Nucleotídeo Único
5.
Nat Commun ; 10(1): 2588, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197172

RESUMO

The brain is a genomic mosaic shaped by cellular responses to genome damage. Here, we manipulate somatic genome stability by conditional Knl1 deletion from embryonic mouse brain. KNL1 mutations cause microcephaly and KNL1 mediates the spindle assembly checkpoint, a safeguard against chromosome missegregation and aneuploidy. We find that following Knl1 deletion, segregation errors in mitotic neural progenitor cells give rise to DNA damage on the missegregated chromosomes. This triggers rapid p53 activation and robust apoptotic and microglial phagocytic responses that extensively eliminate cells with somatic genome damage, thus causing microcephaly. By leaving only karyotypically normal progenitors to continue dividing, these mechanisms provide a second safeguard against brain somatic aneuploidy. Without Knl1 or p53-dependent safeguards, genome-damaged cells are not cleared, alleviating microcephaly, but paradoxically leading to total pre-weaning lethality. Thus, mitotic genome damage activates robust responses to eliminate somatic mutant cells, which if left unpurged, can impact brain and organismal fitness.


Assuntos
Aneuploidia , Microcefalia/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Células-Tronco Neurais/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/genética , Segregação de Cromossomos/genética , Dano ao DNA/genética , Modelos Animais de Doenças , Embrião de Mamíferos , Instabilidade Genômica , Humanos , Cinetocoros/metabolismo , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Cultura Primária de Células , Deleção de Sequência , Fuso Acromático/metabolismo
6.
DNA Cell Biol ; 38(8): 747-753, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31188020

RESUMO

Aberrant neutrophil (PMN) infiltration of the intestinal mucosa is a hallmark of inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. While the genotoxic function of PMNs and its implications in carcinogenesis have been primarily associated with oxidative stress, recent work by Butin-Israeli and colleagues has defined a novel mechanism where PMN-derived microparticles through the delivery and activity of specific miRNAs promoted formation of double-strand breaks (DSBs), and in parallel, suppressed DSB repair through the downregulation of lamin B1 and Rad51. Respective downregulation of these two proteins compromised the nuclear envelope and high-fidelity repair by homologous recombination, increasing DSB accumulation and aneuploidy. This discovery defined a novel mode of action where PMN-mediated suppression of DSB repair leading to genomic instability in the injured mucosa may facilitate progression toward colorectal cancer.


Assuntos
Instabilidade Genômica , Doenças Inflamatórias Intestinais/tratamento farmacológico , Neutrófilos/patologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Quebras de DNA de Cadeia Dupla , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Lamina Tipo B/genética , Lamina Tipo B/metabolismo , MicroRNAs/metabolismo , Neutrófilos/fisiologia , Estresse Oxidativo/genética , Espécies Reativas de Oxigênio/metabolismo
7.
Cancer Treat Rev ; 77: 29-34, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31195213

RESUMO

Gastric Cancer (GC) is a complex and heterogeneous disease, which represents a global health concern. Despite advances in prevention, diagnosis, and therapy, GC is still a leading cause of cancer-related death. Over the last decade, several clinical trials have tested novel agents for advanced GC with mostly disappointing results. Heterogeneity, the absence of molecular selection in clinical trials and powerless predictive biomarkers may be potential explanations. Different molecular classification proposals for GC based on the genetic, epigenetic, and molecular signatures have been published. Molecular characterization of GC may offer new tools for more effective therapeutic strategies, such as the development of therapies for specifically well-defined sets of patients as well as the use of new clinical trial designs, which will ultimately lead to an improvement of medical management of this disease. However, the possibilities of implementation of GC molecular classifications on daily practice and their therapeutic implications remain challenging to date. In this review, we will describe and compare these GC molecular classifications, focusing on their main characteristics as the basis for their potential therapeutic implications and strategies for their clinical application. Key Message: A better understanding of gastric cancer molecular characteristics may lead to further improvements in treatment and outcomes for patients with the disease.


Assuntos
Neoplasias Gástricas/classificação , Instabilidade Genômica , Humanos , Estadiamento de Neoplasias , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
8.
Biochim Biophys Acta Rev Cancer ; 1872(1): 60-65, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31152819

RESUMO

Hepatocellular carcinoma (HCC), the most common form of liver cancer, represents a health problem in hepatic viruses-eradicating era because obesity, type 2 diabetes, and nonalcoholic steatohepatitis (NASH) are considered emerging pathogenic factors. Metabolic disorders underpin mitotic errors that lead to numerical and structural chromosome aberrations in a significant proportion of cell divisions. Here, we review that genomically unstable HCCs show evidence for a paradoxically DNA damage response (DDR) which leads to ongoing chromosome segregation errors. The understanding of DDR induced by defective mitoses is crucial to our ability to develop or improve liver cancer therapeutic strategies.


Assuntos
Carcinoma Hepatocelular/genética , Genoma Humano/genética , Instabilidade Genômica/genética , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/patologia , Instabilidade Cromossômica/genética , Segregação de Cromossomos/genética , Dano ao DNA/genética , Humanos , Neoplasias Hepáticas/patologia , Mitose/genética
9.
World J Microbiol Biotechnol ; 35(5): 77, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31069553

RESUMO

Ethylene is a volatile alkene which is used in large commercial scale as a precursor in plastic industry, and is currently derived from petroleum refinement. As an alternative production strategy, photoautotrophic cyanobacteria Synechocystis sp. PCC 6803 and Synechococcus elongatus PCC 7942 have been previously evaluated as potential biotechnological hosts for producing ethylene directly from CO2, by the over-expression of ethylene forming enzyme (efe) from Pseudomonas syringae. This work addresses various open questions related to the use of Synechococcus as the engineering target, and demonstrates long-term ethylene production at rates reaching 140 µL L-1 h-1 OD750-1 without loss of host vitality or capacity to produce ethylene. The results imply that the genetic instability observed earlier may be associated with the expression strategies, rather than efe over-expression, ethylene toxicity or the depletion of 2-oxoglutarate-derived cellular precursors in Synechococcus. In context with literature, this study underlines the critical differences in expression system design in the alternative hosts, and confirms Synechococcus as a suitable parallel host for further engineering.


Assuntos
Etilenos/biossíntese , Engenharia Metabólica/métodos , Fotossíntese/fisiologia , Synechococcus/genética , Synechococcus/metabolismo , Biotecnologia , Dióxido de Carbono/metabolismo , Clonagem Molecular , Tolerância a Medicamentos , Escherichia coli/genética , Etilenos/toxicidade , Regulação Bacteriana da Expressão Gênica , Genes Bacterianos/genética , Instabilidade Genômica , Ácidos Cetoglutáricos/metabolismo , Liases/genética , Liases/metabolismo , Pseudomonas syringae/genética , Pseudomonas syringae/metabolismo , Synechococcus/efeitos dos fármacos , Synechococcus/crescimento & desenvolvimento , Transformação Genética
10.
BMC Cancer ; 19(1): 434, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077166

RESUMO

BACKGROUND: Chromosomal rearrangements are the typical phenomena in cancer genomes causing gene disruptions and fusions, corruption of regulatory elements, damage to chromosome integrity. Among the factors contributing to genomic instability are non-B DNA structures with stem-loops and quadruplexes being the most prevalent. We aimed at investigating the impact of specifically these two classes of non-B DNA structures on cancer breakpoint hotspots using machine learning approach. METHODS: We developed procedure for machine learning model building and evaluation as the considered data are extremely imbalanced and it was required to get a reliable estimate of the prediction power. We built logistic regression models predicting cancer breakpoint hotspots based on the densities of stem-loops and quadruplexes, jointly and separately. We also tested Random Forest models varying different resampling schemes (leave-one-out cross validation, train-test split, 3-fold cross-validation) and class balancing techniques (oversampling, stratification, synthetic minority oversampling). RESULTS: We performed analysis of 487,425 breakpoints from 2234 samples covering 10 cancer types available from the International Cancer Genome Consortium. We showed that distribution of breakpoint hotspots in different types of cancer are not correlated, confirming the heterogeneous nature of cancer. It appeared that stem-loop-based model best explains the blood, brain, liver, and prostate cancer breakpoint hotspot profiles while quadruplex-based model has higher performance for the bone, breast, ovary, pancreatic, and skin cancer. For the overall cancer profile and uterus cancer the joint model shows the highest performance. For particular datasets the constructed models reach high predictive power using just one predictor, and in the majority of the cases, the model built on both predictors does not increase the model performance. CONCLUSION: Despite the heterogeneity in breakpoint hotspots' distribution across different cancer types, our results demonstrate an association between cancer breakpoint hotspots and stem-loops and quadruplexes. Approximately for half of the cancer types stem-loops are the most influential factors while for the others these are quadruplexes. This fact reflects the differences in regulatory potential of stem-loops and quadruplexes at the tissue-specific level, which yet to be discovered at the genome-wide scale. The performed analysis demonstrates that influence of stem-loops and quadruplexes on breakpoint hotspots formation is tissue-specific.


Assuntos
Pontos de Quebra do Cromossomo , DNA/química , Neoplasias/genética , DNA/genética , Feminino , Heterogeneidade Genética , Instabilidade Genômica , Humanos , Modelos Logísticos , Aprendizado de Máquina , Masculino , Conformação de Ácido Nucleico , Especificidade de Órgãos
11.
Genome Biol Evol ; 11(5): 1432-1439, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31065672

RESUMO

During the last two decades, there has been a public health concern of severe invasive infections caused by Group A Streptococcus (GAS) of the emm1 genotype. This study investigated the dynamics of emm1 GAS during 1994-2013 in Belgium. emm1 GAS isolated from blood, tissue, and wounds of patients with invasive infections (n = 23, S1-S23), and from patients with uncomplicated pharyngitis (n = 15, NS1-NS15) were subjected to whole-genome mapping (WGM; kpn) (Opgen). Whole-genome sequencing was performed on 25 strains (WGS; S1-S23 and NS6-NS7) (Illumina Inc.). Belgian GAS belonged to the M1T1 clone typified by the 36-kb chromosomal region encoding extracellular toxins, NAD+-glycohydrolase and streptolysin O. Strains from 1994-1999 clustered together with published strains (MGAS5005 and M1476). From 2001 onward, invasive GAS showed higher genomic divergence in the accessory genome and harbored on average 7% prophage content. Low evolutionary rate (2.49E-008; P > 0.05) was observed in this study, indicating a highly stable genome. The studied invasive and pharyngitis isolates were no genetically distinct populations based on the WGM and core genome phylogeny analyses. Two copies of the speJ superantigen were present in the 1999 and 2010 study strains (n = 3), one being chromosomal and one being truncated and associated with phage remnants. This study showed that emm1 GAS in Belgium, compared with Canada and UK M1 strains, were highly conserved by harboring a remarkable genome stability over a 19-year period with variations observed in the accessory genome.


Assuntos
Genoma Bacteriano , Instabilidade Genômica , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/genética , Bélgica/epidemiologia , Farmacorresistência Bacteriana/genética , Evolução Molecular , Sequências Repetitivas Dispersas , Infecções Estreptocócicas/epidemiologia , Superantígenos/genética , Sequenciamento Completo do Genoma
12.
Appl Microbiol Biotechnol ; 103(12): 4869-4880, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31053912

RESUMO

The yeast Saccharomyces cerevisiae has been widely used as a model system for studying the physiological and pharmacological action of small-molecular drugs. Here, a heterozygous diploid S. cerevisiae strain QSS4 was generated to determine whether drugs could induce chromosomal instability by determining the frequency of mitotic recombination. Using the combination of a custom SNP microarray and yeast screening system, the patterns of chromosomal instability induced by drugs were explored at the whole genome level in QSS4. We found that Zeocin (a member of the bleomycin family) treatment increased the rate of genomic alterations, including aneuploidy, loss of heterozygosity (LOH), and chromosomal rearrangement over a hundred-fold. Most recombination events are likely to be initiated by DNA double-stand breaks directly generated by Zeocin. Another remarkable finding is that G4-motifs and low GC regions were significantly underrepresented within the gene conversion tracts of Zeocin-induced LOH events, indicating that certain DNA regions are less preferred Zeocin-binding sites in vivo. This study provides a novel paradigm for evaluating genetic toxicity of small-molecular drugs using yeast models.


Assuntos
Instabilidade Cromossômica/efeitos dos fármacos , Cromossomos Fúngicos , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Aneuploidia , Bleomicina/farmacologia , Divisão Celular , Rearranjo Gênico , Instabilidade Genômica , Perda de Heterozigosidade , Recombinação Genética
13.
Cell Mol Life Sci ; 76(18): 3543-3551, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31129857

RESUMO

Maintenance of genomic stability during cell division is one of the most important cellular tasks, and it critically depends on the faithful replication of the genetic material and its equal partitioning into daughter cells, gametes, or spores in the case of yeasts. Defective mitotic spindle assembly and disassembly both result in changes in cellular ploidy that ultimately impinge proliferation fitness and might increase tumor malignancy. Although a great progress has been made in understanding how spindles are assembled to orchestrate chromosome segregation, much less is known about how they are disassembled once completed their function. Here, we review two recently uncovered mechanisms of spindle disassembly that operate at different stages of the fission yeast life cycle.


Assuntos
Schizosaccharomyces/metabolismo , Fuso Acromático/fisiologia , Transporte Ativo do Núcleo Celular , Instabilidade Genômica , Carioferinas/metabolismo , Meiose , Mitose , Membrana Nuclear/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo
14.
World J Microbiol Biotechnol ; 35(6): 79, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31134410

RESUMO

The methylotrophic yeast Pichia pastoris is widely used in recombinant expression of eukaryotic proteins owing to the ability of post-translational modification, tightly regulated promoters, and high cell density fermentation. However, episomal plasmids for heterologous gene expression and the CRISPR/Cas9 system for genome editing have not been well developed in P. pastoris. In the present study, a panel of episomal plasmids containing various autonomously replicating sequences (ARSs) were constructed and their performance in transformation efficiency, copy numbers, and propagation stability were systematically compared. Among the five ARSs with different origins, panARS isolated from Kluyveromyces lactis was determined to have the best performance and used to develop an efficient CRISPR/Cas9 based genome editing system. Compared with a previously reported system using the endogenous and most commonly used ARS (PARS1), the CRISPR/Cas9 genome editing efficiency was increased for more than tenfold. Owing to the higher plasmid stability with panARS, efficient CRISPR/Cas9-mediated genome editing with a type III promoter (i.e. SER promoter) to drive the expression of the single guide RNA (sgRNA) was achieved for the first time. The constructed episomal plasmids and developed CRISPR/Cas9 system will be important synthetic biology tools for both fundamental studies and industrial applications of P. pastoris.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Engenharia Genética/métodos , Pichia/genética , Plasmídeos/genética , Transformação Genética , Replicação do DNA , Escherichia coli/genética , Dosagem de Genes , Regulação Fúngica da Expressão Gênica , Técnicas de Inativação de Genes , Vetores Genéticos , Instabilidade Genômica , Microbiologia Industrial , Kluyveromyces/genética , Regiões Promotoras Genéticas , RNA Guia , Biologia Sintética
15.
Genes Dev ; 33(15-16): 1008-1026, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31123061

RESUMO

Genome replication involves dealing with obstacles that can result from DNA damage but also from chromatin alterations, topological stress, tightly bound proteins or non-B DNA structures such as R loops. Experimental evidence reveals that an engaged transcription machinery at the DNA can either enhance such obstacles or be an obstacle itself. Thus, transcription can become a potentially hazardous process promoting localized replication fork hindrance and stress, which would ultimately cause genome instability, a hallmark of cancer cells. Understanding the causes behind transcription-replication conflicts as well as how the cell resolves them to sustain genome integrity is the aim of this review.


Assuntos
Replicação do DNA/fisiologia , Instabilidade Genômica/genética , Transcrição Genética/fisiologia , Genoma/genética , Humanos , Neoplasias/fisiopatologia , Elongação da Transcrição Genética/fisiologia
16.
Nat Commun ; 10(1): 1635, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30967556

RESUMO

Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.


Assuntos
Cordoma/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Reparo de DNA por Recombinação/genética , Adulto , Idoso , Cordoma/genética , Cordoma/patologia , Mapeamento Cromossômico , Quebras de DNA de Cadeia Dupla , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Instabilidade Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Medicina de Precisão/métodos , Domínios Proteicos/genética , Resultado do Tratamento , Sequenciamento Completo do Exoma
17.
Genes Cells ; 24(5): 377-389, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30929290

RESUMO

In Caenorhabditis elegans, germline cells remain transcriptionally silenced during embryogenesis. The transcriptional silencing is achieved by two different mechanisms: One is the inhibition of RNA polymerase II in P2-P4 cells at the establishment stage, and another is chromatin-based silencing in two primordial germ cells (PGCs) at the maintenance stage; however, the molecular mechanism underlying chromatin-based silencing is less understood. We investigated the role of the chromodomain protein MRG-1, which is an essential maternal factor for germline development, in transcriptional silencing in PGCs. PGCs lacking maternal MRG-1 showed increased levels of two histone modifications (H3K4me2 and H4K16ac), which are epigenetic markers for active transcription, and precocious activation of germline promoters. Loss of MES-4, a H3K36 methyltransferase, also caused similar derepression of the germline genes in PGCs, suggesting that both MRG-1 and MES-4 function in chromatin-based silencing in PGCs. In addition, the mrg-1 null mutant showed abnormal chromosome structures and a decrease in homologous recombinase RAD-51 foci in PGCs, but the mes-4 null mutant did not show such phenotypes. Taken together, we propose that MRG-1 has two distinct functions: chromatin-based transcriptional silencing and preserving genomic integrity at the maintenance stage of PGCs.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Cromatina/genética , Regulação da Expressão Gênica no Desenvolvimento , Inativação Gênica , Células Germinativas/metabolismo , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Cromatina/metabolismo , Instabilidade Genômica , Células Germinativas/citologia , Código das Histonas , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo
18.
J Biomed Sci ; 26(1): 28, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31014351

RESUMO

Cervical cancer is the fourth most frequent cancer in women worldwide and a major cause of mortality in developing countries. Persistent infection with high-risk human papillomavirus (HPV) is a necessary cause for the development of cervical cancer. In addition, genetic and epigenetic alterations in host cell genes are crucial for progression of cervical precancerous lesions to invasive cancer. Although much progress has been made in understanding the life cycle of HPV and it's role in the development of cervical cancer, there is still a critical need for accurate surveillance strategies and targeted therapeutic options to eradicate these cancers in patients. Given the widespread nature of HPV infection and the type specificity of currently available HPV vaccines, it is crucial that molecular details of the natural history of HPV infection as well as the biological activities of viral oncoproteins be elucidated. A better understanding of the mechanisms involved in oncogenesis can provide novel insights and opportunities for designing effective therapeutic approaches against HPV-associated malignancies. In this review, we briefly summarize epigenetic alterations and events that cause alterations in host genomes inducing cell cycle deregulation, aberrant proliferation and genomic instability contributing to tumorigenesis.


Assuntos
Carcinogênese , Papillomaviridae/fisiologia , Infecções por Papillomavirus , Carcinogênese/genética , Ciclo Celular , Proliferação de Células , Epigênese Genética , Feminino , Instabilidade Genômica/genética , Humanos , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/fisiopatologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/fisiopatologia
19.
Biol Pharm Bull ; 42(4): 531-537, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930412

RESUMO

DNA suffers various types of damage even in a normal condition, although they are rapidly repaired by mechanisms called DNA repair. Most progeroid syndromes are caused by genetic defects in specific molecules involved in the DNA repair. DNA damage activates a broad range of signaling pathway that leads to repair, cell cycle arrest, apoptosis and so on, which is called DNA damage response. Recent studies revealed that persistent DNA damage response triggers induction of cell senescence and senescence-associated secretory phenotype (SASP). Here, we review recent advances in the understanding of the molecular mechanisms by which SASP components are regulated, and discuss the possible roles of DNA damage and the DNA damage response, and SASP in the pathogenesis of cardiovascular disease.


Assuntos
Doenças Cardiovasculares , Senescência Celular , Dano ao DNA , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Instabilidade Genômica , Humanos , Inflamação/genética , Inflamação/patologia
20.
Int J Mol Sci ; 20(7)2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30970566

RESUMO

The mammalian mediator complex subunit 28 (MED28) is overexpressed in a variety of cancers and it regulates cell migration/invasion and epithelial-mesenchymal transition. However, transcription factors that increase MED28 expression have not yet been identified. In this study, we performed a luciferase reporter assay to identify and characterize the prospective transcription factors, namely E2F transcription factor 1, nuclear respiratory factor 1, E-26 transforming sequence 1, and CCAAT/enhancer-binding protein ß, which increased MED28 expression. In addition, the release from the arrest at the G1-S or G2-M phase transition after cell cycle synchronization using thymidine or nocodazole, respectively, showed enhanced MED28 expression at the G1-S transition and mitosis. Furthermore, the overexpression of MED28 significantly decreased the duration of interphase and mitosis. Conversely, a knockdown of MED28 using si-RNA increased the duration of interphase and mitosis. Of note, the overexpression of MED28 significantly increased micronucleus and nuclear budding in HeLa cells. In addition, flow cytometry and fluorescence microscopy analyses showed that the overexpression of MED28 significantly increased aneuploid cells. Taken together, these results suggest that MED28 expression is increased by oncogenic transcription factors and its overexpression disturbs the cell cycle, which results in genomic instability and aneuploidy.


Assuntos
Instabilidade Genômica , Complexo Mediador/genética , Complexo Mediador/metabolismo , Fatores de Transcrição/metabolismo , Aneuploidia , Ciclo Celular/efeitos dos fármacos , Instabilidade Genômica/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , Nocodazol/farmacologia , Regiões Promotoras Genéticas , Timidina/farmacologia , Regulação para Cima
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