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1.
Anticancer Res ; 41(7): 3261-3270, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230120

RESUMO

BACKGROUND/AIM: Chronic inflammation generates large quantities of reactive oxygen and nitrogen species that damage DNA. DNA repair is important for cellular viability and genome integrity. MATERIALS AND METHODS: Expression levels of the DNA repair proteins OGG1, XPA, MLH1, PARP1, and XRCC6, which function in base excision repair, nucleotide excision repair, mismatch repair, single-strand break repair and double-strand break repair, respectively, were assessed using immunohistochemistry in ulcerative colitis and sporadic colorectal cancer biopsies. Levels of oxidative/ nitrosative stress biomarkers were also assessed. RESULTS: Ulcerative colitis and colorectal cancer lesions expressed significantly higher levels of all DNA repair proteins and oxidative/ nitrosative stress biomarkers compared to normal colonic mucosa. Ulcerative colitis had the highest XPA and XRCC6 expression. CONCLUSION: Oxidative/nitrosative stress is prevalent in the colon of both diseases. Nucleotide excision repair and non-homologous end-joining double-strand break repair may be compromised in colorectal cancer, but not in ulcerative colitis.


Assuntos
Colite Ulcerativa/genética , Neoplasias Colorretais/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , DNA/genética , Estresse Nitrosativo/genética , Estresse Oxidativo/genética , Biomarcadores Tumorais/genética , Colite Ulcerativa/patologia , Colo/patologia , Neoplasias Colorretais/patologia , Dano ao DNA/genética , Humanos , Mucosa Intestinal/patologia , Oxirredução
2.
FASEB J ; 35(8): e21753, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34233068

RESUMO

Ovarian infertility and subfertility presenting with premature ovarian insufficiency (POI) and diminished ovarian reserve are major issues facing the developed world due to the trend of delaying childbirth. Ovarian senescence and POI represent a continuum of physiological/pathophysiological changes in ovarian follicle functions. Based on advances in whole exome sequencing, evaluation of gene copy variants, together with family-based and genome-wide association studies, we discussed genes responsible for POI and ovarian senescence. We used a gene-centric approach to sort out literature deposited in the Ovarian Kaleidoscope database (http://okdb.appliedbioinfo.net) by sub-categorizing candidate genes as ligand-receptor signaling, meiosis and DNA repair, transcriptional factors, RNA metabolism, enzymes, and others. We discussed individual gene mutations found in POI patients and verification of gene functions in gene-deleted model organisms. Decreased expression of some of the POI genes could be responsible for ovarian senescence, especially those essential for DNA repair, meiosis and mitochondrial functions. We propose to set up a candidate gene panel for targeted sequencing in POI patients together with studies on mitochondria-associated genes in middle-aged subfertile patients.


Assuntos
Ovário/metabolismo , Insuficiência Ovariana Primária/genética , Animais , Reparo do DNA/genética , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla , Humanos , Meiose/genética , Menopausa Precoce/genética , Menopausa Precoce/metabolismo , Modelos Genéticos , Reserva Ovariana/genética , Insuficiência Ovariana Primária/metabolismo , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma
3.
Int J Mol Sci ; 22(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066883

RESUMO

Nucleotide excision repair (NER) resolves DNA adducts, such as those caused by ultraviolet light. Deficient NER (dNER) results in a higher mutation rate that can predispose to cancer development and premature ageing phenotypes. Here, we used isogenic dNER model cell lines to establish a gene expression signature that can accurately predict functional NER capacity in both cell lines and patient samples. Critically, none of the identified NER deficient cell lines harbored mutations in any NER genes, suggesting that the prevalence of NER defects may currently be underestimated. Identification of compounds that induce the dNER gene expression signature led to the discovery that NER can be functionally impaired by GSK3 inhibition, leading to synergy when combined with cisplatin treatment. Furthermore, we predicted and validated multiple novel drugs that are synthetically lethal with NER defects using the dNER gene signature as a drug discovery platform. Taken together, our work provides a dynamic predictor of NER function that may be applied for therapeutic stratification as well as development of novel biological insights in human tumors.


Assuntos
Reparo do DNA/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias/tratamento farmacológico , Neoplasias/genética , Linhagem Celular Tumoral , Humanos , Reprodutibilidade dos Testes
4.
Braz J Biol ; 83: e243910, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34190757

RESUMO

Nucleotide excision repair (NER) acts repairing damages in DNA, such as lesions caused by cisplatin. Xeroderma Pigmentosum complementation group C (XPC) protein is involved in recognition of global genome DNA damages during NER (GG-NER) and it has been studied in different organisms due to its importance in other cellular processes. In this work, we studied NER proteins in Trypanosoma cruzi and Trypanosoma evansi, parasites of humans and animals respectively. We performed three-dimensional models of XPC proteins from T. cruzi and T. evansi and observed few structural differences between these proteins. In our tests, insertion of XPC gene from T. evansi (TevXPC) in T. cruzi resulted in slower cell growth under normal conditions. After cisplatin treatment, T. cruzi overexpressing its own XPC gene (TcXPC) was able to recover cell division rates faster than T. cruzi expressing TevXPC gene. Based on these tests, it is suggested that TevXPC (being an exogenous protein in T. cruzi) interferes negatively in cellular processes where TcXPC (the endogenous protein) is involved. This probably occurred due interaction of TevXPC with some endogenous molecules or proteins from T.cruzi but incapacity of interaction with others. This reinforces the importance of correctly XPC functioning within the cell.


Assuntos
Trypanosoma cruzi , Xeroderma Pigmentoso , Animais , Biologia Computacional , Dano ao DNA/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Trypanosoma cruzi/genética
5.
Aging (Albany NY) ; 13(12): 16696-16712, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158412

RESUMO

In this study, we performed a bioinformatics analysis to identify immune checkpoint genes (ICGs) associated with prognosis and the immunotherapeutic response in endometrial carcinoma (EC) patients. We classified 47 ICGs into high, medium, and low expression groups by performing RNA-sequencing data analysis of EC patient samples from The Cancer Genome Atlas (n = 521) and GSE77688 (n = 88) datasets. Univariate Cox regression analysis showed that seven ICGs (VTCN1, TNFRSF18, TNFRSF14, TNFRSF4, CD40LG, TMIGD2, and BTLA) were associated with prognosis in EC patients. Spearman correlation analysis showed that prognosis-related ICGs correlated positively with immunotherapy response factors, including tumor mutation burden (TMB), mismatch repair gene mutations, neoantigens, clinical stages, and adaptive immune resistance pathway genes. We identified a prognostic gene signature of four ICGs (IDO1, CD274, CTLA4, and TNFRSF14) that accurately predicted survival outcomes of EC patients. TIMER database and Kaplan-Meier survival analysis showed that OS among EC patients with low TNFRSF14 expression was significantly shorter than among those with high TNFRSF14 expression. In vitro experiments showed that TNFRSF14 silencing increased the migration and invasiveness of EC cells by promoting epithelial-mesenchymal transition (EMT). Collectively, these findings reveal an immune checkpoint gene signature that accurately predicts survival outcomes and immunotherapeutic responses in EC patients.


Assuntos
Neoplasias do Endométrio/genética , Neoplasias do Endométrio/terapia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Checkpoint Imunológico/genética , Imunoterapia , Imunidade Adaptativa/genética , Antígenos de Neoplasias , Reparo do DNA/genética , Bases de Dados Genéticas , Resistência à Doença/genética , Neoplasias do Endométrio/imunologia , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Mutação/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Prognóstico , Análise de Sobrevida
6.
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
7.
Mutat Res ; 787: 108347, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083046

RESUMO

APE2 is a rising vital player in the maintenance of genome and epigenome integrity. In the past several years, a series of studies have shown the critical roles and functions of APE2. We seek to provide the first comprehensive review on several aspects of APE2 in genome and epigenome integrity. We first summarize the distinct functional domains or motifs within APE2 including EEP (endonuclease/exonuclease/phosphatase) domain, PIP box and Zf-GRF motifs from eight species (i.e., Homo sapiens, Mus musculus, Xenopus laevis, Ciona intestinalis, Arabidopsis thaliana, Schizosaccharomyces pombe, Saccharomyces cerevisiae, and Trypanosoma cruzi). Then we analyze various APE2 nuclease activities and associated DNA substrates, including AP endonuclease, 3'-phosphodiesterase, 3'-phosphatase, and 3'-5' exonuclease activities. We also examine several APE2 interaction proteins, including PCNA, Chk1, APE1, Myh1, and homologous recombination (HR) factors such as Rad51, Rad52, BRCA1, BRCA2, and BARD1. Furthermore, we provide insights into the roles of APE2 in various DNA repair pathways (base excision repair, single-strand break repair, and double-strand break repair), DNA damage response (DDR) pathways (ATR-Chk1 and p53-dependent), immunoglobulin class switch recombination and somatic hypermutation, as well as active DNA demethylation. Lastly, we summarize critical functions of APE2 in growth, development, and diseases. In this review, we provide the first comprehensive perspective which dissects all aspects of the multiple-function protein APE2 in genome and epigenome integrity.


Assuntos
Proteínas de Arabidopsis/genética , Endonucleases/genética , Animais , Proteínas de Arabidopsis/metabolismo , Dano ao DNA/genética , Dano ao DNA/fisiologia , Desmetilação do DNA , Reparo do DNA/genética , Reparo do DNA/fisiologia , Epigenoma/genética , Humanos , Imunidade/genética , Imunidade/fisiologia , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
8.
Mutat Res ; 787: 108362, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083050

RESUMO

Radiotherapy is one of the primary modalities for cancer treatment, and its efficiency usually relies on cellular radiosensitivity. DNA damage repair is a core content of cellular radiosensitivity, and the primary mechanism of which includes non-homologous end-joining (NHEJ) and homologous recombination (HR). By affecting DNA damage repair, histone methylation regulated by histone methyltransferases (HMTs) and histone demethylases (HDMs) participates in the regulation of cellular radiosensitivity via three mechanisms: (a) recruiting DNA repair-related proteins, (b) regulating the expressions of DNA repair genes, and (c) mediating the dynamic change of chromatin. Interestingly, both aberrantly high and low levels of histone methylation could impede DNA repair processes. Here we reviewed the mechanisms of the dual effects of histone methylation on cell response to radiation. Since some inhibitors of HMTs and HDMs are reported to increase cellular radiosensitivity, understanding their molecular mechanisms may be helpful in developing new drugs for the therapy of radioresistant tumors.


Assuntos
Histona Desmetilases/metabolismo , Histona Metiltransferases/metabolismo , Histonas/metabolismo , Reparo do DNA/genética , Reparo do DNA/fisiologia , Feminino , Histona Desmetilases/genética , Histona Metiltransferases/genética , Histonas/genética , Humanos , Masculino , Tolerância a Radiação
9.
Nat Commun ; 12(1): 4033, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34188037

RESUMO

In response to DNA double-strand breaks (DSBs), repair proteins are recruited to the damaged sites. Ubiquitin signaling plays a critical role in coordinating protein recruitment during the DNA damage response. Here, we find that the microRNA biogenesis factor DGCR8 promotes tumor resistance to X-ray radiation independently of its Drosha-binding ability. Upon radiation, the kinase ATM and the deubiquitinase USP51 mediate the activation and stabilization of DGCR8 through phosphorylation and deubiquitination. Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs. This, in turn, promotes ubiquitination of histone H2A, repair of DSBs, and radioresistance. Altogether, these findings reveal the non-canonical function of DGCR8 in DSB repair and suggest that radiation treatment may result in therapy-induced tumor radioresistance through ATM- and USP51-mediated activation and upregulation of DGCR8.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Proteínas de Ligação a RNA/metabolismo , Tolerância a Radiação/genética , Proteases Específicas de Ubiquitina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Enzimas Desubiquitinantes/metabolismo , Células HCT116 , Células HEK293 , Células HeLa , Células Hep G2 , Histonas/metabolismo , Humanos , Células MCF-7 , Neoplasias/genética , Neoplasias/radioterapia , Fosforilação , Proteínas de Ligação a RNA/genética , Ubiquitina-Proteína Ligases/metabolismo
10.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065507

RESUMO

Small ubiquitin-like modifier (SUMO)-targeted E3 ubiquitin ligases (STUbLs) are specialized enzymes that recognize SUMOylated proteins and attach ubiquitin to them. They therefore connect the cellular SUMOylation and ubiquitination circuits. STUbLs participate in diverse molecular processes that span cell cycle regulated events, including DNA repair, replication, mitosis, and transcription. They operate during unperturbed conditions and in response to challenges, such as genotoxic stress. These E3 ubiquitin ligases modify their target substrates by catalyzing ubiquitin chains that form different linkages, resulting in proteolytic or non-proteolytic outcomes. Often, STUbLs function in compartmentalized environments, such as the nuclear envelope or kinetochore, and actively aid in nuclear relocalization of damaged DNA and stalled replication forks to promote DNA repair or fork restart. Furthermore, STUbLs reside in the same vicinity as SUMO proteases and deubiquitinases (DUBs), providing spatiotemporal control of their targets. In this review, we focus on the molecular mechanisms by which STUbLs help to maintain genome stability across different species.


Assuntos
Instabilidade Genômica/genética , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Sumoilação/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina/genética , Animais , Reparo do DNA/genética , Humanos
11.
Front Public Health ; 9: 647563, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34164366

RESUMO

We tested the hypothesis that differences in DNA double-strand break (DSB) repair fidelity underlies differences in individual radiosensitivity and, consequently, normal tissue reactions to radiotherapy. Fibroblast cultures derived from a radio-sensitive (RS) breast cancer patient with grade 3 adverse reactions to radiotherapy were compared with normal control (NC) and hyper-radiosensitive ataxia-telangiectasia mutated (ATM) cells. DSB repair and repair fidelity were studied by Southern blotting and hybridization to Alu repetitive sequence and to a specific 3.2-Mbp NotI restriction fragment on chromosome 21, respectively. Results for DNA repair kinetics using the NotI fidelity assay showed significant differences (P < 0.001) with higher levels of misrepaired (misrejoined and unrejoined) DSBs in RS and ATM compared with NC. At 24-h postradiation, the relative fractions of misrepaired DSBs were 10.64, 23.08, and 44.70% for NC, RS, and ATM, respectively. The Alu assay showed significant (P < 0.05) differences in unrepaired DSBs only between the ATM and both NC and RS at the time points of 12 and 24 h. At 24 h, the relative percentages of DSBs unrepaired were 1.33, 3.43, and 12.13% for NC, RS, and ATM, respectively. The comparison between the two assays indicated an average of 5-fold higher fractions of misrepaired (NotI assay) than unrepaired (Alu assay) DSBs. In conclusion, this patient with increased radiotoxicity displayed more prominent misrepaired than unrepaired DSBs, suggesting that DNA repair fidelity is a potential marker for the adverse reactions to radiotherapy. More studies are required to confirm these results and further develop DSB repair fidelity as a hallmark biomarker for interindividual differences in radiosensitivity.


Assuntos
Ataxia Telangiectasia , Neoplasias da Mama , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Reparo do DNA/genética , Feminino , Humanos , Tolerância a Radiação/genética
12.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067421

RESUMO

Base Excision Repair (BER) addresses base lesions and abasic sites induced by exogenous and endogenous stressors. X-ray cross complementing group 1 (XRCC1) functions as a scaffold protein in BER and single-strand break repair (SSBR), facilitating and coordinating repair through its interaction with a host of critical repair proteins. Alterations of XRCC1 protein and gene expression levels are observed in many cancers, including colorectal, ovarian, and breast cancer. While increases in the expression level of XRCC1 are reported, the transcription factors responsible for this up-regulation are not known. In this study, we identify the signal transducer and activator of transcription 3 (STAT3) as a novel regulator of XRCC1 through chromatin immunoprecipitation. Activation of STAT3 through phosphorylation at Y705 by cytokine (IL-6) signaling increases the expression of XRCC1 and the occupancy of STAT3 within the XRCC1 promoter. In triple negative breast cancer, the constitutive activation of STAT3 upregulates XRCC1 gene and protein expression levels. Increased expression of XRCC1 is associated with aggressiveness and resistance to DNA damaging chemotherapeutics. Thus, we propose that activated STAT3 regulates XRCC1 under stress and growth conditions, but constitutive activation in cancers results in dysregulation of XRCC1 and subsequently BER and SSBR.


Assuntos
Regiões Promotoras Genéticas/genética , Fator de Transcrição STAT3/genética , Neoplasias de Mama Triplo Negativas/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Linhagem Celular , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Simples , Dano ao DNA/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Interleucina-6/genética , Fosforilação/genética , Regulação para Cima/genética
13.
Anticancer Res ; 41(5): 2333-2347, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952458

RESUMO

BACKGROUND/AIM: Glioblastoma multiforme (GBM) is a lethal disease with a high rate of chemoresistance to temozolomide (TMZ). The aim of the study was to establish a TMZ-resistant subline from the GBM-8401 cell line to determine the mechanisms of resistance and identify novel effective therapeutics for TMZ-resistant GBM. MATERIALS AND METHODS: Comparative transcriptome analysis of GBM-8401/TMZR cells and the parental line was performed using Ion Torrent sequencing. Differentially expressed genes (DEGs) between the GBM-8401/TMZR and GBM-8401 cell lines were analyzed. RESULTS: Transcriptomic profiling of GBM-8401/TMZR cells revealed DEGs involved in the retinoblastoma (RB) signaling, DNA damage response (DDR) pathway, and DNA repair mechanisms. CONCLUSION: In vitro and in vivo cell-based GBM models should be used in further biomedical studies to investigate the underlying mechanisms of TMZ-resistant GBM.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Temozolomida/farmacologia , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Dano ao DNA , Reparo do DNA/genética , Relação Dose-Resposta a Droga , Glioblastoma/patologia , Humanos , Modelos Genéticos , Proteína do Retinoblastoma/genética , Transdução de Sinais/genética
14.
EMBO Rep ; 22(5): e51851, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33932076

RESUMO

Defects in DNA single-strand break repair (SSBR) are linked with neurological dysfunction but the underlying mechanisms remain poorly understood. Here, we show that hyperactivity of the DNA strand break sensor protein Parp1 in mice in which the central SSBR protein Xrcc1 is conditionally deleted (Xrcc1Nes-Cre ) results in lethal seizures and shortened lifespan. Using electrophysiological recording and synaptic imaging approaches, we demonstrate that aberrant Parp1 activation triggers seizure-like activity in Xrcc1-defective hippocampus ex vivo and deregulated presynaptic calcium signalling in isolated hippocampal neurons in vitro. Moreover, we show that these defects are prevented by Parp1 inhibition or deletion and, in the case of Parp1 deletion, that the lifespan of Xrcc1Nes-Cre mice is greatly extended. This is the first demonstration that lethal seizures can be triggered by aberrant Parp1 activity at unrepaired SSBs, highlighting PARP inhibition as a possible therapeutic approach in hereditary neurological disease.


Assuntos
Cálcio , Proteínas de Ligação a DNA , Animais , DNA , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Camundongos , Neurônios/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Convulsões/genética
15.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946818

RESUMO

Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.


Assuntos
Adenocarcinoma/secundário , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Neoplasias de Próstata Resistentes à Castração/terapia , Adenocarcinoma/terapia , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Ensaios Clínicos como Assunto , Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos , Previsões , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Masculino , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Estudos Multicêntricos como Assunto , Proteínas de Neoplasias/antagonistas & inibidores , Compostos Organoplatínicos/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Medicina de Precisão/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Taxoides/administração & dosagem
16.
Mol Cell Biol ; 41(7): e0008221, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-33941620

RESUMO

Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. Conserved from yeast to humans, vigilin is an RNA-binding protein with 14 tandemly arranged nonidentical hnRNP K-type homology (KH) domains. Here, we report that vigilin depletion increased cell sensitivity to cisplatin- or ionizing radiation (IR)-induced cell death and genomic instability due to defective DNA repair. Vigilin depletion delayed dephosphorylation of IR-induced γ-H2AX and elevated levels of residual 53BP1 and RIF1 foci, while reducing Rad51 and BRCA1 focus formation, DNA end resection, and double-strand break (DSB) repair. We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. Transient hydroxyurea (HU)-induced replicative stress in vigilin-depleted cells increased replication fork stalling and blocked restart of DNA synthesis. Furthermore, histone acetylation promoted vigilin recruitment to DSBs preferentially in the transcriptionally active genome. These findings uncover a novel vigilin role in DNA damage repair with implications for autism and cancer-related disorders.


Assuntos
Transtorno Autístico/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Instabilidade Genômica/fisiologia , Proteína BRCA1 , Reparo do DNA/fisiologia , Replicação do DNA/genética , Instabilidade Genômica/genética , Humanos , Proteínas de Ligação a RNA/metabolismo , Rad51 Recombinase/genética
17.
Aging (Albany NY) ; 13(10): 14277-14288, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34016790

RESUMO

UCHL3 belongs to the UCH family and is involved in multiple biological processes. However, the biological functions and underlying mechanisms of action of UCHL3 in radio-sensitivity of non-small cell lung cancer (NSCLC) remain unknown. Here, we reported that the expression of UCHL3 was significantly up-regulated in NSCLC tissues and cell lines, and associated with poor prognosis of NSCLC patients. The expression of UCHL3 of NSCLC cells was increased after exposure to ionizing radiation (IR). Moreover, we found that knockdown of UCHL3 enhanced the radio-sensitivity of NSCLC cells both in vitro and in vivo. Furthermore, γH2AX foci staining and Western blot analysis showed that knockdown of UCHL3 increased IR-induced DNA damage. Knockdown of UCHL3 in NSCLC cells decreased homologous recombination (HR) repair efficiency and RAD51 foci formation. Collectively, our study revealed that knockdown of UCHL3 enhanced the radio-sensitivity of NSCLC cells and increased IR-induced DNA damage via impairing HR repair.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Reparo do DNA/genética , Inativação Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Tolerância a Radiação/genética , Ubiquitina Tiolesterase/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/efeitos da radiação , Dano ao DNA/genética , Regulação Neoplásica da Expressão Gênica , Recombinação Homóloga/genética , Humanos , Camundongos Nus , Prognóstico , Radiação Ionizante , Ubiquitina Tiolesterase/metabolismo , Regulação para Cima/genética
18.
Nucleic Acids Res ; 49(10): 5779-5797, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34048572

RESUMO

Faithful genome integrity maintenance plays an essential role in cell survival. Here, we identify the RNA demethylase ALKBH5 as a key regulator that protects cells from DNA damage and apoptosis during reactive oxygen species (ROS)-induced stress. We find that ROS significantly induces global mRNA N6-methyladenosine (m6A) levels by modulating ALKBH5 post-translational modifications (PTMs), leading to the rapid and efficient induction of thousands of genes involved in a variety of biological processes including DNA damage repair. Mechanistically, ROS promotes ALKBH5 SUMOylation through activating ERK/JNK signaling, leading to inhibition of ALKBH5 m6A demethylase activity by blocking substrate accessibility. Moreover, ERK/JNK/ALKBH5-PTMs/m6A axis is activated by ROS in hematopoietic stem/progenitor cells (HSPCs) in vivo in mice, suggesting a physiological role of this molecular pathway in the maintenance of genome stability in HSPCs. Together, our study uncovers a molecular mechanism involving ALKBH5 PTMs and increased mRNA m6A levels that protect genomic integrity of cells in response to ROS.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Dano ao DNA , Reparo do DNA , Espécies Reativas de Oxigênio/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Desmetilação/efeitos dos fármacos , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metilação/efeitos dos fármacos , Camundongos , Fosforilação , Processamento de Proteína Pós-Traducional , RNA Interferente Pequeno , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , RNA-Seq , Sumoilação/efeitos dos fármacos , Espectrometria de Massas em Tandem , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismo
19.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809300

RESUMO

Alzheimer's disease (AD), the most common form of neurodegenerative dementia in adults worldwide, is a multifactorial and heterogeneous disorder characterized by the interaction of genetic and epigenetic factors and the dysregulation of numerous intracellular signaling and cellular/molecular pathways. The introduction of the systems biology framework is revolutionizing the study of complex diseases by allowing the identification and integration of cellular/molecular pathways and networks of interaction. Here, we reviewed the relationship between physical activity and the next pathophysiological processes involved in the risk of developing AD, based on some crucial molecular pathways and biological process dysregulated in AD: (1) Immune system and inflammation; (2) Endothelial function and cerebrovascular insufficiency; (3) Apoptosis and cell death; (4) Intercellular communication; (5) Metabolism, oxidative stress and neurotoxicity; (6) DNA damage and repair; (7) Cytoskeleton and membrane proteins; (8) Synaptic plasticity. Moreover, we highlighted the increasingly relevant role played by advanced neuroimaging technologies, including structural/functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labelling, in exploring the link between AD and physical exercise. Regular physical exercise seems to have a protective effect against AD by inhibiting different pathophysiological molecular pathways implicated in AD.


Assuntos
Doença de Alzheimer/terapia , Exercício Físico/fisiologia , Estresse Oxidativo/fisiologia , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/reabilitação , Dano ao DNA/genética , Reparo do DNA/genética , Imagem de Tensor de Difusão/métodos , Humanos , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Transdução de Sinais/genética
20.
Mol Biol (Mosk) ; 55(2): 181-193, 2021.
Artigo em Russo | MEDLINE | ID: mdl-33871434

RESUMO

The base and nucleotide excision DNA repair (BER and NER) systems are aimed at removing specific types of damaged DNA, i.e., oxidized, alkylated, or deaminated bases in the case of BER and bulky damage caused by UV radiation or chemical carcinogens in the case of NER. In some cases, however, the repair process follows a more complex scenario, which implies that the repair pathways exchange proteins and interact with each other to form a common interactome. This review describes the BER and NER mechanisms and discusses the current data on the involvement of the NER proteins in the repair of DNA lesions caused by oxidative stress and the BER proteins in the removal of bulky DNA adducts. We also discuss the role of poly(ADP-ribose) polymerase 1 in the regulation of the BER and NER processes and their coordination in the repair of complex (cluster) lesions.


Assuntos
Dano ao DNA , Reparo do DNA , DNA/genética , DNA/metabolismo , Reparo do DNA/genética , Nucleotídeos , Estresse Oxidativo/genética
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