RESUMO
Self-DNA is present in the cytosol of many cancer cells and can promote effective immune rejection of tumor cells, but the mechanisms leading to the presence of cytosolic DNA are unknown. Here, we report that the cleavage of genomic DNA by DNA structure-specific endonuclease MUS81 and PARP-dependent DNA repair pathways leads to the accumulation of cytosolic DNA in prostate cancer cells. The number of nuclear MUS81 foci and the amount of cytosolic dsDNA increased in tandem from hyperplasia to clinical stage II prostate cancers and decreased at stage III. Cytosolic DNA generated by MUS81 stimulated DNA sensor STING-dependent type I interferon (IFN) expression and promoted phagocytic and T cell responses, resulting in type I and II IFN-mediated rejection of prostate tumor cells via mechanisms that partly depended on macrophages. Our results demonstrate that the tumor suppressor MUS81 alerts the immune system to the presence of transformed host cells.
Assuntos
Autoantígenos/metabolismo , Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Endonucleases/metabolismo , Neoplasias da Próstata/imunologia , Linfócitos T/imunologia , Animais , Autoantígenos/imunologia , Linhagem Celular Tumoral , DNA/imunologia , Humanos , Interferon Tipo I/metabolismo , Ativação Linfocitária , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estadiamento de Neoplasias , Neoplasias Experimentais , Fagocitose , Neoplasias da Próstata/patologiaRESUMO
It has been established that up to 8.3% of the biallelic coding SNPs present in dbSNP are actually artefactual polymorphism-like errors, previously termed single nucleotide differences, or SNDs. In this study, a previous analysis of SNPs in dbSNP was extended and updated to examine how the incidence of SNDs has changed over an intervening five year period. The incidence of SNDs was found to be lower than in the previous analysis at 2.2% of all biallelic SNPs. There was only a modest reduction in the percentage of SNDs in the original set of biallelic coding SNPs tested. This suggests that the overall reduction in the incidence of SNDs over the intervening 5-year period is related to an improvement in SNP detection methods and more rigorous curation, rather than efforts to ameliorate the presence of SNDs. We note that SNDs contaminating the dbSNP may lead to erroneous conclusions on human conditions.
Assuntos
Bases de Dados Genéticas/normas , Polimorfismo de Nucleotídeo Único , Artefatos , Genoma Humano , Estudo de Associação Genômica Ampla , Genômica , HumanosRESUMO
We recently provided evidence that genome-derived DNA is present in the cytosol of many tumor cells. Genomic loci that give rise to cytosolic DNA can potentially form non-B DNA structures including triple-stranded RNA:DNA structures (R-loops). The RNA:DNA-specific endonuclease RNaseh1 reduced the levels of cytosolic DNA and type I interferon-dependent rejection of B-cell lymphoma suggesting that cytosolic DNA may contribute to immune surveillance of B-cell lymphoma.
Assuntos
DNA/genética , Genoma , Interferon Tipo I/genética , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Linhagem Celular Tumoral , Humanos , RNA/genéticaRESUMO
The creation of single nucleotide polymorphism (SNP) databases (such as NCBI dbSNP) has facilitated scientific research in many fields. SNP discovery and detection has improved to the extent that there are over 17 million human reference (rs) SNPs reported to date (Build 129 of dbSNP). SNP databases are unfortunately not always complete and/or accurate. In fact, half of the reported SNPs are still only candidate SNPs and are not validated in a population. We describe the identification of SNDs (single nucleotide differences) in humans, that may contaminate the dbSNP database. These SNDs, reported as real SNPs in the database, do not exist as such, but are merely artifacts due to the presence of a paralogue (highly similar duplicated) sequence in the genome. Using sequencing we showed how SNDs could originate in two paralogous genes and evaluated samples from a population of 100 individuals for the presence/absence of SNPs. Moreover, using bioinformatics, we predicted as many as 8.32% of the biallelic, coding SNPs in the dbSNP database to be SNDs. Our identification of SNDs in the database will allow researchers to not only select truly informative SNPs for association studies, but also aid in determining accurate SNP genotypes and haplotypes.
Assuntos
Bases de Dados Genéticas , Erros de Diagnóstico , Estudos de Associação Genética/métodos , Genoma Humano/genética , Haplótipos/genética , Polimorfismo de Nucleotídeo Único/genética , Aurora Quinases , Biologia Computacional/métodos , Genótipo , Humanos , Internet , Proteínas Serina-Treonina Quinases/genéticaRESUMO
Recent success in immunomodulating strategies in lung cancer and melanoma has prompted much enthusiasm in their potential to treat other advanced solid malignancies. However, their applications have shown variable success and are even ineffective against some tumours. The efficiency of immunotherapies relies on an immunogenic tumour microenvironment. The current field of cancer immunology has focused on understanding the interaction of cancer and host immune cells to break the state of immune tolerance and explain how molecular patterns of cytokines and chemokines affect tumour progression. Here, we review our current knowledge of how inherent properties of tumours and their different tumour microenvironments affect therapeutic outcome. We also discuss insights into recent multimodal therapeutic approaches that target tumour immune evasion and suppression to restore anti-tumour immunity.
Assuntos
Imunoterapia/métodos , Humanos , Microambiente TumoralRESUMO
The presence of damaged and microbial DNA can pose a threat to the survival of organisms. Cells express various sensors that recognize specific aspects of such potentially dangerous DNA. Recognition of damaged or microbial DNA by sensors induces cellular processes that are important for DNA repair and inflammation. Here, we review recent evidence that the cellular response to DNA damage and microbial DNA are tightly intertwined. We also discuss insights into the parameters that enable DNA sensors to distinguish damaged and microbial DNA from DNA present in healthy cells.
Assuntos
Bactérias/imunologia , Reparo do DNA/imunologia , DNA Bacteriano/imunologia , Animais , Bactérias/genética , Reparo do DNA/genética , DNA Bacteriano/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologiaRESUMO
Vitamin D has long been known for its physiological role in mineral homeostasis through its actions on the intestines, kidneys, parathyroid glands and bone. However, recent observations of antiproliferative, prodifferentiating and antiangiogenic effects elicited by the bioactive form of vitamin D (1,25[OH](2)D(3)) in a broad range of cancers is less well understood. Here, we review the increasing epidemiological and experimental evidence that supports the development of 1,25(OH)(2)D(3) and vitamin D analogs as preventative and therapeutic anticancer agents. Furthermore, this review summarizes the preclinical and clinical studies of vitamin D and its analogs over the past decade, indicating the current problems of dose-limiting toxicity from hypercalcemia and large interpatient variability in pharmacokinetics. A better understanding of how genetic variants influence vitamin D status should not only improve cancer risk predictions, but also promote the development of vitamin D analogs with more specific actions to improve therapeutic outcomes.