Articles

Original Article
Open access

Efficient CRISPR/Cas9 mediated large insertions using long single-stranded oligonucleotide donors in C. elegans

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The use of ssDNA as repair templates provides a major advantage over dsDNA when inserting large fragments into the Caenorhabditis elegans genome with CRISPR/Cas9. A simple PCR followed by strand-selective digestion by lambda exonuclease facilitates the efficient generation of the ssDNA. Frequently, over 50% of progeny are edited, enabling simultaneous double insertions and marker-free recovery.

Original Article
Open access

Increased demand for FAD synthesis in differentiated and stem pancreatic cancer cells is accomplished by modulating FLAD1 gene expression: the inhibitory effect of Chicago Sky Blue

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FAD production, a crucial process for cell metabolism, is ensured by FAD synthase (FADS), coded by FLAD1. FLAD1 expression and FADS enzymatic activity significantly increase in pancreatic ductal adenocarcinoma cells and derived stem cells compared to non-malignant cells. Higher cofactor availability parallels increased levels of FAD-dependent enzymes. Thinking of FADS as a novel therapeutic target, an enzymatic inhibitor, Chicago Sky Blue, was introduced, which was able to selectively inhibit stem cell growth.

Original Article
Open access

Identification of a diketopiperazine-based O-GlcNAc transferase inhibitor sensitizing hepatocellular carcinoma to CDK9 inhibition

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The post-translational process O-GlcNAcylation is implicated in a variety of physiological processes and diseases, including hepatocellular carcinoma. Here, we identified HLY838, a novel diketopiperazine-based OGT inhibitor that induces a global decrease in cellular O-GlcNAcylation. HLY838 enhances the anti-HCC activity of CDK9 inhibitors both in vitro and in vivo by downregulating c-Myc and E2F1 expression. Our findings suggest that targeting O-GlcNAcylation with HLY838 may be an effective strategy to improve cancer therapy.

Original Article

Regulation of PARP1 and its apoptotic variant activity by single-stranded DNA

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DNA breaks recognition stimulates the catalytic activity of PARP1. Here, we have shown that Zinc-finger domains of PARP1 bind to single-strand DNA (ssDNA). Also, ssDNA acts as an activator of PARP1 activity, while poly-ADP ribose (PAR) partially hampers the ssDNA-dependent stimulation by inducing DNA dissociation. We have demonstrated that the catalytic apoptotic fragment of PARP1 is stimulated by ssDNA when complemented with a regulatory apoptotic fragment.

Review
Open access

New insights into the structure and function of CNNM proteins

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Cystathionine-β-synthase-pair domain divalent metal cation transport mediators (CNNMs) are a newly characterized class of Mg2+ transporters associated with a variety of human diseases. CNNMs are ubiquitous and found in all kingdoms of life. Here, we review recent structural and functional studies of CNNMs that have identified the transmembrane channel and clarified the regulatory role of the cytosolic domains.

Review
free access

The role of lysosomal membrane proteins in autophagy and related diseases

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Some of the roles of lysosome membrane proteins in autophagy, with a focus on their roles in vesicular nucleation, vesicular elongation and completion, fusion of autophagosomes and lysosomes, degradation, and their extensive association with related diseases.

State‐of‐the‐Art Review
Open access

New insights into the function and pathophysiology of the ectodomain sheddase A Disintegrin And Metalloproteinase 10 (ADAM10)

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There is an increasing appreciation that the A Disintegrin And Metalloproteinase 10 (ADAM10) is of importance in health and disease. This review aims to summarize recent findings referring to the cell biology and pathophysiological implications of ADAM10. Its role in common and rare diseases is discussed here, with the goal to unravel ADAM10's translational potential as a target for pharmacological intervention or its use as a biomarker.

Original Article
Open access

Biochemical and structural insight into the chemical resistance and cofactor specificity of the formate dehydrogenase from Starkeya novella

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The biochemical and structural investigation of a bacterial formate dehydrogenase sheds light on its remarkable chemical resistance to thiol-modifying compounds. The strict specificity for the coenzyme NAD+ is changed by targeted amino acid mutations at the binding site to make the enzyme specific for NADP+. The cofactor-bound structure of a high-affinity mutant for NADP+ offers a mechanistic explanation of the successful change in cofactor specificity.

State‐of‐the‐Art Review
Open access

Hallmarks and evolutionary drivers of cotranslational protein complex assembly

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Cotranslational assembly is a widespread mechanism for the formation of protein complexes in cells. This process depends on five hallmarks: the spatial proximity, temporal coordination, energetic stability, composition and topological arrangement of the interacting subunits. Although experiments and structural analyses have identified many properties of cotranslationally assembled complexes, their evolutionary origins and trajectories remain still largely unknown.

Commentary

Screen time: an unbiased search for histone mutations that affect quiescence and chronological aging

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Quiescence is essential for survival during nutrient limitations and the execution of precise developmental patterns. In yeast, entry into quiescence is associated with a loss of histone acetylation as the chromatin becomes tightly condensed. In this issue, Small and Osley performed an unbiased screen of mutations in histone H3 and H4 amino acids in budding yeast and identified histone residues that are critical for quiescence and chronological lifespan.

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