BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM

Information professionals and copyright literacy: a multinational study

Purpose: The purpose of this paper is to present findings from a multinational survey on copyright literacy of specialists from libraries and other cultural institutions. Design/methodology/approach: This paper is based on a multinational survey of copyright literacy competencies of Library and Information Science (LIS) professionals and those who work in the cultural heritage sector (archives and museums), conducted in 13 countries, namely Bulgaria (BG), Croatia (CR), Finland (FI), France (FR), Hungary (HU), Lithuania (LT), Mexico (MX), Norway (NO), Portugal (PT), Romania (RO), Turkey (TR), UK and USA in the period July 2013-March 2015. An online survey instrument was developed in order to collect data from professionals regarding their familiarity with, knowledge and awareness of, and opinions on copyright-related issues. Findings: Findings of this study highlight gaps in existing knowledge of copyright, and information about the level of copyright literacy of LIS and cultural sector professionals. Also attitudes toward copyright learning content in academic education and continuing professional development training programs are investigated. Originality/value: This study aimed to address a gap in the literature by encompassing specialists from the cultural institutions in an international comparative context. The paper offers guidance for further understanding of copyright in a wider framework of digital and information literacy; and for the implementation of copyright policy, and the establishment of copyright advisor positions in cultural institutions. The recommendations support a revision of academic and continuing education programs learning curriculum and methods

Associations between a polymorphism in the pleiotropic GCKR and Age-related phenotypes: the HALCyon programme.

Background: The glucokinase regulatory protein encoded by GCKR plays an important role in glucose metabolism and a single nucleotide polymorphism (SNP) rs1260326 (P446L) in the gene has been associated with several age-related biomarkers, including triglycerides, glucose, insulin and apolipoproteins. However, associations between SNPs in the gene and other ageing phenotypes such as cognitive and physical capability have not been reported. Methods: As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women from five UK cohorts aged between 44 and 90+ years were genotyped for rs1260326. Meta-analysis was used to pool within-study genotypic associations between the SNP and several age-related phenotypes, including body mass index (BMI), blood lipid levels, lung function, and cognitive and physical capability. Results: We confirm the associations between the minor allele of the SNP and higher triglycerides and lower glucose levels. We also observed a triglyceride-independent association between the minor allele and lower BMI (pooled beta on zscore = 20.04, p-value = 0.0001, n = 16,251). Furthermore, there was some evidence for gene-environment interactions, including physical activity attenuating the effects on triglycerides. However, no associations were observed with measures of cognitive and physical capability. Conclusion: Findings from middle-aged to older adults confirm associations between rs1260326 GCKR and triglycerides and glucose, suggest possible gene-environment interactions, but do not provide evidence that its relevance extends to cognitive and physical capability

Classification of msh6 variants of uncertain significance using functional assays

Lynch syndrome (LS) is one of the most common hereditary cancer predisposition syndromes worldwide. Individuals with LS have a high risk of developing colorectal or endometrial cancer, as well as several other cancers. LS is caused by autosomal dominant pathogenic variants in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, PMS2 or MSH6, and typically include truncating variants, such as frameshift, nonsense or splicing variants. However, a significant number of missense, intronic, or silent variants, or small in-frame insertions/deletions, are detected during genetic screening of the MMR genes. The clinical effects of these variants are often more difficult to predict, and a large fraction of these variants are classified as variants of uncertain significance (VUS). It is pivotal for the clinical management of LS patients to have a clear genetic diagnosis, since patients benefit widely from screening, preventive and personal therapeutic measures. Moreover, in families where a pathogenic variant is identified, testing can be offered to family members, where non-carriers can be spared frequent surveillance, while carriers can be included in cancer surveillance programs. It is therefore important to reclassify VUSs, and, in this regard, functional assays can provide insight into the effect of a variant on the protein or mRNA level. Here, we briefly describe the disorders that are related to MMR deficiency, as well as the structure and function of MSH6. Moreover, we review the functional assays that are used to examine VUS identified in MSH6 and discuss the results obtained in relation to the ACMG/AMP PS3/BS3 criterion. We also provide a compiled list of the MSH6 variants examined by these assays. Finally, we provide a future perspective on high-throughput functional analyses with specific emphasis on the MMR genes

Increased deoxythymidine triphosphate levels is a feature of relative cognitive decline

Mitochondrial bioenergetics, mitochondrial reactive oxygen species (ROS) and cellular levels of nucleotides have been hypothesized as early indicators of Alzheimer’s disease (AD). Utilizing relative decline of cognitive ability as a predictor of AD risk, we evaluated the correlation between change of cognitive ability and mitochondrial bioenergetics, ROS and cellular levels of deoxyribonucleotides. Change of cognitive abilities, scored at ages of approximately 20 and 57 was determined for a cohort of 1985 male participants. Mitochondrial bioenergetics, mitochondrial ROS and whole-cell levels of deoxyribonucleotide triphosphates were measured in peripheral blood mononuclear cells (PBMCs) from a total of 103 selected participants displaying the most pronounced relative cognitive decline and relative cognitive improvement. We show that relative cognitive decline is associated with higher PBMC content of deoxythymidine-triphosphate (dTTP) (20%), but not mitochondrial bioenergetics parameters measured in this study or mitochondrial ROS. Levels of dTTP in PBMCs are indicators of relative cognitive change suggesting a role of deoxyribonucleotides in the etiology of AD

ETHE1-p.Arg163Gln and p.Arg163Trp mutations affect the mononuclear iron site reduction potential.

<p><b>A</b>. EPR spectra of ETHE1 proteins at 1 mg.ml⁻¹ in 150 mM Tris-HCl pH 7.5 and 300 mM NaCl. <b>B</b>. Redox titrations followed by EPR spectroscopy. Solid and dashed lines are Nernst Curves obtained for the different ETHE1 proteins one-electron reduction processes (n = 1) and the oxidation-reduction potentials are listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0107157#pone-0107157-t001" target="_blank">Table 1</a>. EPR spectra were recorded at 9.39 GHz microwave frequency, 2 mW microwave power, 1 mT modulation amplitude, 8 K temperature.</p