DNA Glycosylases Define the Outcome of Endogenous Base Modifications.

Chemically modified nucleic acid bases are sources of genomic instability and mutations but may also regulate gene expression as epigenetic or epitranscriptomic modifications. Depending on the cellular context, they can have vastly diverse impacts on cells, from mutagenesis or cytotoxicity to changing cell fate by regulating chromatin organisation and gene expression. Identical chemical modifications exerting different functions pose a challenge for the cell's DNA repair machinery, as it needs to accurately distinguish between epigenetic marks and DNA damage to ensure proper repair and maintenance of (epi)genomic integrity. The specificity and selectivity of the recognition of these modified bases relies on DNA glycosylases, which acts as DNA damage, or more correctly, as modified bases sensors for the base excision repair (BER) pathway. Here, we will illustrate this duality by summarizing the role of uracil-DNA glycosylases, with particular attention to SMUG1, in the regulation of the epigenetic landscape as active regulators of gene expression and chromatin remodelling. We will also describe how epigenetic marks, with a special focus on 5-hydroxymethyluracil, can affect the damage susceptibility of nucleic acids and conversely how DNA damage can induce changes in the epigenetic landscape by altering the pattern of DNA methylation and chromatin structure.

hGSuite HyperBrowser: A web-based toolkit for hierarchical metadata-informed analysis of genomic tracks.

Many high-throughput sequencing datasets can be represented as objects with coordinates along a reference genome. Currently, biological investigations often involve a large number of such datasets, for example representing different cell types or epigenetic factors. Drawing overall conclusions from a large collection of results for individual datasets may be challenging and time-consuming. Meaningful interpretation often requires the results to be aggregated according to metadata that represents biological characteristics of interest. In this light, we here propose the hierarchical Genomic Suite HyperBrowser (hGSuite), an open-source extension to the GSuite HyperBrowser platform, which aims to provide a means for extracting key results from an aggregated collection of high-throughput DNA sequencing data. The hGSuite utilizes a metadata-informed data cube to calculate various statistics across the multiple dimensions of the datasets. With this work, we show that the hGSuite and its associated data cube methodology offers a quick and accessible way for exploratory analysis of large genomic datasets. The web-based toolkit named hGsuite Hyperbrowser is available at https://hyperbrowser.uio.no/hgsuite under a GPLv3 license.

Dynamic features of human mitochondrial DNA maintenance and transcription.

Mitochondria are the primary sites for cellular energy production and are required for many essential cellular processes. Mitochondrial DNA (mtDNA) is a 16.6 kb circular DNA molecule that encodes only 13 gene products of the approximately 90 different proteins of the respiratory chain complexes and an estimated 1,200 mitochondrial proteins. MtDNA is, however, crucial for organismal development, normal function, and survival. MtDNA maintenance requires mitochondrially targeted nuclear DNA repair enzymes, a mtDNA replisome that is unique to mitochondria, and systems that control mitochondrial morphology and quality control. Here, we provide an overview of the current literature on mtDNA repair and transcription machineries and discuss how dynamic functional interactions between the components of these systems regulate mtDNA maintenance and transcription. A profound understanding of the molecular mechanisms that control mtDNA maintenance and transcription is important as loss of mtDNA integrity is implicated in normal process of aging, inflammation, and the etiology and pathogenesis of a number of diseases.

C. elegans as an Animal Model to Study the Intersection of DNA Repair, Aging and Neurodegeneration.

Since its introduction as a genetic model organism, Caenorhabditis elegans has yielded insights into the causes of aging. In addition, it has provided a molecular understanding of mechanisms of neurodegeneration, one of the devastating effects of aging. However, C. elegans has been less popular as an animal model to investigate DNA repair and genomic instability, which is a major hallmark of aging and also a cause of many rare neurological disorders. This article provides an overview of DNA repair pathways in C. elegans and the impact of DNA repair on aging hallmarks, such as mitochondrial dysfunction, telomere maintenance, and autophagy. In addition, we discuss how the combination of biological characteristics, new technical tools, and the potential of following precise phenotypic assays through a natural life-course make C. elegans an ideal model organism to study how DNA repair impact neurodegeneration in models of common age-related neurodegenerative diseases.

Phaeochromocytomas overexpress insulin transcript and produce insulin.

INTRODUCTION: Phaeochromocytomas are tumours originating in the medulla of the adrenal gland. They produce catecholamines, and some tumours also produce ectopic hormones. Two types of glucose imbalances occur in phaeochromocytoma patients, hyperglycaemia and hypoglycaemic attacks. Therefore, we tested whether insulin transcript (INS), insulin, and a hybrid read-through transcript between exons from insulin and insulin-like growth factor 2 (INS-IGF2) were expressed in phaeochromocytomas. METHODS: We measured the expression of insulin using immunohistochemistry. The expression of INS-IGF2 was determined by qRT-PCR in formalin-fixed and paraffin-embedded tissue from 20 phaeochromocytomas. The expression of INS and INS-IGF2 transcriptswas also analysed in 182 phaeochromocytomas and paragangliomas using publicly available datasets in The Cancer Genome Atlas (TCGA) Database. RESULTS: Of 20 phaeochromocytomas, 16 stained positive for insulin. The distribution of positive cells was mostly scattered, with some focal expression indicating clonal expansion. Nineteen tumours expressed high levels of INS and INS-IGF2 transcripts. The expression of the two transcripts corresponded closely. In the TCGA dataset, phaeochromocytoma expresses higher levels of INS and INS-IGF2 transcripts compared to the normal non-tumour adrenal glands. Thus, the expression of INS and INS-IGF2 seems to be a general phenomenon in phaeochromocytoma. CONCLUSION: Most phaeochromocytomas contain cells that overexpress INS and INS-IGF2 transcripts. Most tumours also display heterogeneous expression of polypeptides immunoreactive to monoclonal anti-insulin antibodies. Clinically this may relate to both hyperglycaemia and hypoglycaemic attacks seen in patients with phaeochromocytoma as well as autocrine tumour growth.

Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: A case series.

BACKGROUND: Genetic risk variants in the hemizygous allele may influence neuropsychiatric manifestations and clinical course in 3q29 deletion carriers. METHODS: In-depth phenotypic assessment in two deletion carriers included medical records, medical, genetic, psychiatric and neuropsychological evaluations, brain MRI scan and EEG. Blood samples were analyzed for copy number variations, and deep sequencing of the affected 3q29 region was performed in patients and seven first-degree relatives. Risk variants were identified through bioinformatic analysis. RESULTS: One deletion carrier was diagnosed with learning difficulties and childhood autism, the other with mild intellectual disability and schizophrenia. EEG abnormalities in childhood normalized in adulthood in both. Cognitive abilities improved during adolescence in one deletion carrier. Both had microcytic, hypochromic erythrocytes and suffered from chronic pain and fatigue. Molecular and bioinformatic analyses identified risk variants in the hemizygous allele that were not present in the homozygous state in relatives in genes involved in cilia function and insulin action in the autistic individual and in synaptic function and neurosteroid transport in the subject with schizophrenia. CONCLUSION: 3q29 deletion carriers may undergo developmental phenotypic transition and need regular medical follow-up. Identified risk variants in the remaining hemizygous allele should be explored further in autism and schizophrenia research.