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.
•Presence of cytosolic DNA in prostate cancer cells depends on Mus81•Mus81 induces STING-dependent type I interferon expression•Immune rejection of prostate cancer cells relies on Mus81 and STING•Mus81 enhances innate and adaptive anti-cancer immune responses
The mechanisms leading to the presence of cytosolic DNA in cancer cells are unknown. Gasser and colleagues find that the DNA structure-specific endonuclease Mus81 promotes the shedding of genomic DNA into the cytosol of prostate cancer cells. Mus81 stimulates STING-dependent DNA sensor pathways and immune rejection of prostate cancer cells.
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.
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. Hum Mutat 31:67-73, 2010.
Sensing of dangerous DNA Gasser, Stephan; Zhang, Wendy Y.L.; Tan, Nikki Yi Jie ...
Mechanisms of ageing and development,
July 2017, 2017-07-00, 20170701, Letnik:
165, Številka:
Pt A
Journal Article
Recenzirano
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.
ABSTRACT
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.
Single nucleotide differences (SNDs) are artefactual polymorphism‐like errors present in the NCBI dbSNP database due to paralogue loci. They occur as a result of poor primer design, suboptimal PCR, or the uncritical sequence alignment of ESTs. In this study, we show that 2.2% of all biallelic SNPs are actually artefactual SNDs. This has implications for human genomics, such as erroneous research findings, and perhaps even human health, as SNPs are now used in personalized medicine.
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 (1,25OH(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.
•Genome-derived ssDNA, dsDNA and DNA:RNA hybrids are present in the cytosol of tumor cells.•Cytosolic DNA can potentially form non-B DNA structures.•Cytosolic DNA contributes to type I ...interferon-dependent immune rejection of B-cell lymphoma.
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.
The HIV epidemic in Cameroon is characterized by a high level of strain diversity despite a relatively low prevalence of infection. In this study, HIV strains infecting blood donors in Cameroon were ...characterized to determine the prevalence of subtypes and intersubtype recombinants and if strain prevalence was changing over time.
From 1996 through 2004, 676 HIV-infected blood donations were collected at blood banks in Douala and Yaoundé, Cameroon. A subset of the HIV-1 group M strains (n = 574) were classified based on phylogenetic analysis of viral sequences from the gag p24, pol integrase, and env gp41 regions.
HIV-1 group M accounted for 97.3% (n = 658) of infections, whereas group O was present in 2.2% (n = 15) and HIV-2 in 0.4% (n = 3). Within the group M infections, 14 subtypes and circulating recombinant forms (CRFs) and unique recombinant forms (URFs) were identified. Overall, CRFO2_AG accounted for 58.2% of infections, URFs 14.8%, and levels of subtypes, A, B, C, D, F2, and G, and CRFs, 01, 06, 09, 11, 13, 22, and 37, varied from 0.2% to 6.1%. Evaluation of HIV strains present in the donor population over this 9-year period showed no substantial changes in the proportion of infections caused by each subtype and CRF, the percentage of intersubtype recombinants, or the strain composition of the URFs.
HIV-1 strain diversity in Cameroon did not significantly change, suggesting a mature and relatively stable epidemic.
Inherited mutations in the BRCA1 gene confer increased susceptibility to breast and ovarian cancer. Its role in sporadic carcinogenesis is not well defined. Somatic mutations in breast cancers have ...not been reported and to date there are only three reports of somatic mutations in sporadic ovarian cancers. To investigate the contribution of BRCA1 mutations to sporadic breast and ovarian cancer in the Chinese population, we analysed 62 samples from Chinese women using the protein truncation test. There were 40 cases of breast cancer under age 50 and 22 cases of ovarian cancer, all unselected for family history. There was no age selection for the ovarian cancers. We found two somatic BRCA1 mutations in exon 11, one in a breast cancer and the other in an ovarian cancer, both of which result in truncated proteins. Our results indicate that somatic BRCA1 mutations, like somatic mutations in the BRCA2 gene, though very rare, can be found in both breast and ovarian cancers and support a tumor suppressor function for BRCA1 in sporadic tumors.
Numerous reports of vascular events after an initial recovery from COVID-19 form our impetus to investigate the impact of COVID-19 on vascular health of recovered patients. We found elevated levels ...of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8
T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.
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