Search results for "Helicase"

Comparative genomics and protein domain graph analyses link ubiquitination and RNA metabolism.

2006

The human gene parkin, known to cause familial Parkinson disease, as well as several other genes, likely involved in other neurodegenerative diseases or in cancer, encode proteins of the RBR family of ubiquitin ligases. Here, we describe the structural diversity of the RBR family in order to infer their functional roles. Of particular interest is a relationship detected between RBR-mediated ubiquitination and RNA metabolism: a few RBR proteins contain RNA binding domains and DEAH-box RNA helicase domains. Global protein domain graph analyses demonstrate that this connection is not RBR-specific, but instead many other proteins contain both ubiquitination and RNA-related domains. These protei…

Poly(ADP-ribosyl)ation accelerates DNA repair in a pathway dependent on Cockayne syndrome B protein

2003

Activation of poly(ADP-ribose)polymerases 1 and 2 (PARP-1 and PARP-2) is one of the earliest responses of mammalian cells to DNA damage by numerous genotoxic agents. We have analysed the influence of PARP inhibition, either achieved by over-expression of the DNA binding domain of PARP-1 or by treatment with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone, on the repair of single-strand breaks (SSB), pyrimidine dimers and oxidative base modifications sensitive to Fpg protein (mostly 8-hydroxyguanine) in mammalian cells at very low, non-cytotoxic levels of DNA damage. The data show that the repair rates of all three types of DNA damage are significantly lower in PARP-inhibited c…

Cockayne syndrome: varied requirement of transcription-coupled nucleotide excision repair for the removal of three structurally different adducts fro…

2014

Hereditary defects in the transcription-coupled nucleotide excision repair (TC-NER) pathway of damaged DNA cause severe neurodegenerative disease Cockayne syndrome (CS), however the origin and chemical nature of the underlying DNA damage had remained unknown. To find out, to which degree the structural properties of DNA lesions determine the extent of transcription arrest in human CS cells, we performed quantitative host cell reactivation analyses of expression vectors containing various synthetic adducts. We found that a single 3-(deoxyguanosin-N 2-yl)-2-acetylaminofluorene adduct (dG(N 2)-AAF) constitutes an unsurmountable obstacle to transcription in both CS-A and CS-B cells and is remov…

Late activation of stress kinases (SAPK/JNK) by genotoxins requires the DNA repair proteins DNA-PKcs and CSB.

2005

Although genotoxic agents are powerful inducers of stress kinases (SAPK/JNK), the contribution of DNA damage itself to this response is unknown. Therefore, SAPK/JNK activation of cells harboring specific defects in DNA damage-recognition mechanisms was studied. Dual phosphorylation of SAPK/JNK by the genotoxin methyl methanesulfonate (MMS) occurred in two waves. The early response (≤2 h after exposure) was similar in cells knockout for ATM, PARP, p53, and CSB or defective in DNA-PKcscompared with wild-type cells. The late response however (≥4 h), was drastically reduced in DNA-PKcsand Cockayne's syndrome B (CSB)-deficient cells. Similar results were obtained with human cells lacking DNA-PKc…

Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia

2020

Introduction Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development. Methods To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we perfor…

Sequential recruitment of the mRNA decay machinery to the iron-regulated protein Cth2 in Saccharomyces cerevisiae

2020

Post-transcriptional factors importantly contribute to the rapid and coordinated expression of the multiple genes required for the adaptation of living organisms to environmental stresses. In the model eukaryote Saccharomyces cerevisiae, a conserved mRNA-binding protein, known as Cth2, modulates the metabolic response to iron deficiency. Cth2 is a tandem zinc-finger (TZF)-containing protein that co-transcriptionally binds to adenine/uracil-rich elements (ARE) present in the 3′-untranslated region of iron-related mRNAs to promote their turnover. The nuclear binding of Cth2 to mRNAs via its TZFs is indispensable for its export to the cytoplasm. Although Cth2 nucleocytoplasmic transport is ess…

Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development

2018

AbstractDe novo germline mutations in the RNA helicase DDX3X account for 1-3% of unexplained intellectual disability (ID) cases in females, and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here we use human and mouse genetics, and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n=78), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes.…

8-Oxoguanine DNA glycosylase (Ogg1) causes a transcriptional inactivation of damaged DNA in the absence of functional Cockayne syndrome B (Csb) prote…

2008

We have analysed the effect of oxidative guanine lesions on the expression of a transfected reporter gene in mouse embryonic fibroblasts deficient in Cockayne syndrome B protein (Csb) and/or the 8-oxoguanine DNA glycosylase (Ogg1). We used a highly sensitive flow cytometry-based approach and quantitative real-time PCR to measure the changes in gene expression caused by the presence of oxidised guanine residues generated by photosensitisation in the vector DNA. In wild-type cells, small numbers (one or three) of oxidised guanines did not affect gene expression at short times after transfections, whereas progressive reduction of the transgene expression was observed at later time points. Alth…

IS LA-PROTEIN INVOLVED IN AUTOIMMUNIZATION AND INFLAMMATORY EVENTS DURING DISEASE - CHARACTERIZATION OF LA-PROTEIN AS AN UNWINDING ENZYME

1990

The elemental role of iron in DNA synthesis and repair

2017

Iron is an essential redox element that functions as a cofactor in many metabolic pathways. Critical enzymes in DNA metabolism, including multiple DNA repair enzymes (helicases, nucleases, glycosylases, demethylases) and ribonucleotide reductase, use iron as an indispensable cofactor to function. Recent striking results have revealed that the catalytic subunit of DNA polymerases also contains conserved cysteine-rich motifs that bind iron–sulfur (Fe/S) clusters that are essential for the formation of stable and active complexes. In line with this, mitochondrial and cytoplasmic defects in Fe/S cluster biogenesis and insertion into the nuclear iron-requiring enzymes involved in DNA synthesis a…