Shieldin, including SHLD1, SHLD2, SHLD3 and REV7, functions as a bridge linking 53BP1-RIF1 and single-strand DNA to suppress the DNA termini nucleolytic resection during non-homologous end joining (NHEJ). However, the mechanism of shieldin assembly remains unclear. Here we present the crystal structure of the SHLD3-REV7-SHLD2 ternary complex and reveal an unexpected C (closed)-REV7-O (open)-REV7 conformational dimer mediated by SHLD3. We show that SHLD2 interacts with O-REV7 and the N-terminus of SHLD3 by forming β sheet sandwich. Disruption of the REV7 conformational dimer abolishes the assembly of shieldin and impairs NHEJ efficiency. The conserved FXPWFP motif of SHLD3 binds to C-REV7 and blocks its binding to REV1, which excludes shieldin from the REV1/Pol ζ translesion synthesis (TLS) complex. Our study reveals the molecular architecture of shieldin assembly, elucidates the structural basis of the REV7 conformational dimer, and provides mechanistic insight into orchestration between TLS and NHEJ.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181697 | PMC |
| http://dx.doi.org/10.1038/s41467-020-15879-5 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Background: Small, soluble oligomers, rather than mature fibrils, are the major neurotoxic agents in Alzheimer's disease (AD). In the last few years, Aprile and co-workers designed and purified a single-domain antibody (sdAb), called DesAb-O, with high specificity for Aβ oligomeric conformers. Recently, Cascella and co-workers showed that DesAb-O can selectively detect synthetic Aβ oligomers both in vitro and in cultured cells, neutralizing their associated neuronal dysfunction.
View Article and Find Full Text PDFThe Elusive Ternary Intermediates of Chiral Phosphoric Acids in Ion Pair Catalysis─Structures, Conformations, and Aggregation.
J Am Chem Soc
January 2025
Institute of Organic Chemistry, University Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany.
In ion-pair catalysis, the last intermediate structures prior to the stereoselective transition states are of special importance for predictive models due to the high isomerization barrier between - and -substrate double bonds connecting ground and transition state energies. However, in prior experimental investigations of chiral phosphoric acids (CPA) solely the early intermediates could be investigated while the key intermediate remained elusive. In this study, the first experimental structural and conformational insights into ternary complexes with CPAs are presented using a special combination of low temperature and relaxation optimized N HSQC-NOESY NMR spectroscopy to enhance sensitivity.
View Article and Find Full Text PDFTipping the balance between and ligand conformers in multinuclear ethylzinc cyclophosphazenates.
Dalton Trans
January 2025
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.
Hexaanionic cyclophosphazenate ligands [(RN)PN] provide versatile platforms for the assembly of multinuclear metal arrays due to their multiple coordination sites and highly flexible ligand core structure. This work investigates the impact of incrementally increasing the steric demand of the ligand periphery on the coordination behavior of ethylzinc arrays. It shows that the increased congestion around the ligand sites is alleviated by progressive condensation with the elimination of diethylzinc.
View Article and Find Full Text PDFConformational protection of molybdenum nitrogenase by Shethna protein II.
Nature
January 2025
Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg im Breisgau, Germany.
The oxygen-sensitive molybdenum-dependent nitrogenase of Azotobacter vinelandii is protected from oxidative damage by a reversible 'switch-off' mechanism. It forms a complex with a small ferredoxin, FeSII (ref. ) or the 'Shethna protein II', which acts as an O sensor and associates with the two component proteins of nitrogenase when its [2Fe:2S] cluster becomes oxidized.
View Article and Find Full Text PDFComparative study on gene expression profiles in the liver of male neonatal mice prenatally exposed to PFOA and its alternative HFPO-DA.
Toxicology
January 2025
School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan; Advanced Research Promotion Center, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan. Electronic address:
Hexafluoropropylene oxide dimer acid (HFPO-DA), which belongs to the class of perfluoroalkyl ether carboxylic acid (PFECA), is a new alternative to perfluorooctanoic acid (PFOA). However, whether HFPO-DA is a safer alternative to PFOA in neonates remains unclear. In this study, we evaluated neonatal hepatic toxicity on postnatal days 9-10 by orally exposing pregnant CD-1 mice to 0.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!