The ERCC1-xeroderma pigmentosum group F DNA repair complex

In its long nucleotide-chains, the DNA double helix contains the genetic information for ten thousands of proteins. The DNA molecule, however, is subject to constant change. In order to l11ailltaill its integrity, several luechallisms that cope with DNA damage, inflicted byvarious naturally occurring and man-made agents, have evolved. Individuals with the rare genetic disease xeroderma pigmentosum demonstrate the importance of DNA repair systems. These patients carry a defect in proteins that are involved in the removal ofUV-induced damage from the DNA, which results in sun-sensitivity and the frequent occurrence of skin cancers, Hence, studies on DNA repair and human repah' disorders such as xeroderma pigmentosu

República: Año III Número 346 - (10/08/33)

BACKGROUND: Biomedical knowledge graphs have become important tools to computationally analyse the comprehensive body of biomedical knowledge. They represent knowledge as subject-predicate-object triples, in which the predicate indicates the relationship between subject and object. A triple can also contain provenance information, which consists of references to the sources of the triple (e.g. scientific publications or database entries). Knowledge graphs have been used to classify drug-disease pairs for drug efficacy screening, but existing computational methods have often ignored predicate and provenance information. Using this information, we aimed to develop a supervised machine learning classifier and determine the added value of predicate and provenance information for drug efficacy screening. To ensure the biological plausibility of our method we performed our research on the protein level, where drugs are represented by their drug target proteins, and diseases by their disease proteins. RESULTS: Using random forests with repeated 10-fold cross-validation, our method achieved an area under the ROC curve (AUC) of 78.1% and 74.3% for two reference sets. We benchmarked against a state-of-the-art knowledge-graph technique that does not use predicate and provenance information, obtaining AUCs of 65.6% and 64.6%, respectively. Classifiers that only used predicate information performed superior to classifiers that only used provenance information, but using both performed best. CONCLUSION: We conclude that both predicate and provenance information provide added value for drug efficacy screening

Revealing new leads for the impact of galacto-oligosaccharides on gut commensals and gut health benefits through text mining

Item does not contain fulltextGalacto-oligosaccharides (GOS) are linked to various health benefits, such as the relief of symptoms of constipation. Part of the beneficial effects of GOS are thought to be the consequence of their bifidogenic effect, stimulating the growth of several Bifidobacterium species in vivo. However, GOS may exert additional effects by directly stimulating other bacterial species or by effects that bifidobacteria may have on other commensals in the gut. To get a better insight into the potential health effects induced by GOS, a good understanding of the gut ecosystem, the role of GOS and bifidobacteria is important. An increasing number of 16S DNA profiling and metagenomics studies have led to an expanding inventory of genera, species and strains that can be found in the human gut. To investigate the potential connection of these commensals with GOS and bifidobacteria, we have undertaken a text-mining study to chart the literature landscape around these commensals. To this end, we created controlled vocabularies describing GOS, a large set of gut commensals and a number of terms related to gut health, which were used to mine the entire MEDLINE database. Co-occurrence text-mining revealed that a large number of commensals found in the gut have a connection with Bifidobacterium species and with gut health effects. Word frequency analysis provided more insight into the functional nature of these relationships. Combined co-occurrence search results pointed to putative novel health benefits indirectly linked to bifidobacteria and GOS. The potential beneficial effects of GOS on the protection of epithelial function and epithelial barrier impairment and appendicitis are interesting novel leads. The text-mining approach reported here revealed a number of novel leads through which GOS could exert health effects and that could be investigated in dedicated studies

Least Absolute Regression Network Analysis of the murine osteoblast differentiation network

Item does not contain fulltextMOTIVATION: We propose a reverse engineering scheme to discover genetic regulation from genome-wide transcription data that monitors the dynamic transcriptional response after a change in cellular environment. The interaction network is estimated by solving a linear model using simultaneous shrinking of the least absolute weights and the prediction error. RESULTS: The proposed scheme has been applied to the murine C2C12 cell-line stimulated to undergo osteoblast differentiation. Results show that our method discovers genetic interactions that display significant enrichment of co-citation in literature. More detailed study showed that the inferred network exhibits properties and hypotheses that are consistent with current biological knowledge. AVAILABILITY: Software is freely available for academic use as a Matlab package, called GENLAB: http://genlab.tudelft.nl/genlab.html. SUPPLEMENTARY INFORMATION: Additional data, results and figures can be found at http://genlab.tudelft.nl/larna.html

Mapping of interaction domains between human repair proteins ERCC1 and XPF

ERCC1-XPF is a heterodimeric protein complexinvolved in nucleotide excision repair and recombinational processes. Like its homologous complex in Saccharomyces cerevisiae , Rad10-Rad1, it acts as a structure-specific DNA endonuclease, cleaving at duplex-single-stranded DNA junctions. In repair, ERCC1-XPF and Rad10-Rad1 make an incision on the the 5'-side of the lesion. No humans with a defect in the ERCC1 subunit of this protein complex have been identified and ERCC1-deficient mice suffer from severe developmental problems and signs of premature aging on top of a repair-deficient phenotype. Xeroderma pigmentosum group F patients carry mutations in the XPF subunit and generally show the clinical symptoms of mild DNA repair deficiency. All XP-F patients examined demonstrate reduced levels of XPF and ERCC1 protein, suggesting that proper complex formation is required for stability of the two proteins. To better understand the molecular and clinical consequences of mutations in the ERCC1-XPF complex, we decided to map the interaction domains between the two subunits. The XPF-binding domain comprises C-terminal residues 224-297 of ERCC1. Intriguingly, this domain resides outside the region of homology with its yeast Rad10 counterpart. The ERCC1-b

Microarray analysis on Runx2-deficient mouse embryos reveals novel Runx2 functions and target genes during intramembranous and endochondral bone formation

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Mutational analysis of the human nucleotide excision repair gene ERCC1.

The human DNA repair protein ERCC1 resides in a complex together with the ERCC4, ERCC11 and XP-F correcting activities, thought to perform the 5' strand incision during nucleotide excision repair (NER). Its yeast counterpart, RAD1-RAD10, has an additional engagement in a mitotic recombination pathway, probably required for repair of DNA cross-links. Mutational analysis revealed that the poorly conserved N-terminal 91 amino acids of ERCC1 are dispensable for both repair functions, in contrast to a deletion of only four residues from the C-terminus. A database search revealed a strongly conserved motif in this C-terminus sharing sequence homology with many DNA break processing proteins, indicating that this part is primarily required for the presumed structure-specific endonuclease activity of ERCC1. Most missense mutations in the central region give rise to an unstable protein (complex). Accordingly, we found that free ERCC1 is very rapidly degraded, suggesting that protein-protein interactions provide stability. Survival experiments show that the removal of cross-links requires less ERCC1 than UV repair. This suggests that the ERCC1-dependent step in cross-link repair occurs outside the context of NER and provides an explanation for the phenotype of the human repair syndrome xeroderma pigmentosum group F

Enhancement of damage-specific DNA binding of XPA by interaction with the ERCC1 DNA repair protein

The human XPA and ERCC1 proteins, which are involved in early steps of nucleotide excision repair of DNA, specifically interacted in an in vitro binding assay and a yeast two-hybrid assay. A stretch of consecutive glutamic acid residues in XPA was needed for binding to ERCC1. Binding of XPA to damaged DNA was markedly increased by the interaction of the XPA and ERCC1 proteins. ERCC1 did not enhance binding to DNA when a truncated XPA protein, MF122, was used in place of the XPA protein. MF122 retains damaged DNA binding activity but lacks the region for protein-protein interaction including the E-cluster region. These results suggest that the XPA/ERCC1 interaction may participate in damage-recognition as well as in incision at the 5′ site of damage during nucleotide excision repair