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| http://dx.doi.org/10.1111/bjh.16326 | DOI Listing |
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Inherent asymmetry of Rpd3S coordinates its nucleosome engagement and association with elongating RNA polymerase II.
Nat Struct Mol Biol
January 2025
Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
The Rpd3S histone deacetylase complex has a crucial role in genomic integrity by deacetylating transcribed nucleosomes following RNA polymerase (Pol) II passage. Cryo-EM studies highlight the importance of asymmetrical Rco1-Eaf3 dimers in nucleosome binding, yet the interaction dynamics with nucleosomal substrates alongside elongating Pol II are poorly understood. Here we demonstrate the essential function of the Rco1 N-terminal intrinsically disordered region (IDR) in modulating Pol II association, in which K/R mutations within the Rco1 IDR impair interaction of Rpd3S with the C-terminal domain (CTD) of Rpb1, without affecting nucleosome recognition or complex integrity.
View Article and Find Full Text PDFSite-saturation mutagenesis of 500 human protein domains.
Nature
January 2025
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Missense variants that change the amino acid sequences of proteins cause one-third of human genetic diseases. Tens of millions of missense variants exist in the current human population, and the vast majority of these have unknown functional consequences. Here we present a large-scale experimental analysis of human missense variants across many different proteins.
View Article and Find Full Text PDFKLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency.
Nat Commun
January 2025
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
ATR plays key roles in cellular responses to DNA damage and replication stress, a pervasive feature of cancer cells. ATR inhibitors (ATRi) are in clinical development for treating various cancers, including those with high replication stress, such as is elicited by ARID1A deficiency, but the cellular mechanisms that determine ATRi efficacy in such backgrounds are unclear. Here, we have conducted unbiased genome-scale CRISPR screens in ARID1A-deficient and proficient cells treated with ATRi.
View Article and Find Full Text PDFReconstitution of human DNA licensing and the structural and functional analysis of key intermediates.
Nat Commun
January 2025
DNA Replication Group, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
Human DNA licensing initiates replication fork assembly and DNA replication. This reaction promotes the loading of the hMCM2-7 complex on DNA, which represents the core of the replicative helicase that unwinds DNA during S-phase. Here, we report the reconstitution of human DNA licensing using purified proteins.
View Article and Find Full Text PDF[Clinical and genetic analysis of a child with Lamb-Shaffer syndrome due to a de novo variant of SOX5 gene].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi
January 2025
Department of Clinical Laboratory, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou Key Laboratory of Children's Infection and Immunity, Zhengzhou, Henan 450018, China.
Objective: To explore the clinical features of a child with Lamb-Shaffer syndrome (LAMSHF) due to a variant of SOX5 gene.
Methods: A child who was admitted to Children's Hospital Affiliated to Zhengzhou University in July 2022 was selected as the study subject. Clinical data of the child was collected.
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