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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 PDFInactivation of GSK3β by Ser phosphorylation prevents thymocyte necroptosis and impacts Tcr repertoire diversity.
Cell Death Differ
January 2025
Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA.
The assembly of Tcrb and Tcra genes require double negative (DN) thymocytes to undergo multiple rounds of programmed DNA double-strand breaks (DSBs), followed by their efficient repair. However, mechanisms governing cell cycle checkpoints and specific survival pathways during the repair process remain unclear. Here, we report high-resolution scRNA-seq analyses of individually sorted mouse DN3 and DN4 thymocytes, which reveals a G2M cell cycle checkpoint, in addition to the known G1 checkpoint, during Tcrb and Tcra recombination.
View Article and Find Full Text PDFThe sequence-structure-function relationship of intrinsic ERα disorder.
Nature
January 2025
Case Comprehensive Cancer Center and Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
The oestrogen receptor (ER or ERα), a nuclear hormone receptor that drives most breast cancer, is commonly activated by phosphorylation at serine 118 within its intrinsically disordered N-terminal transactivation domain. Although this modification enables oestrogen-independent ER function, its mechanism has remained unclear despite ongoing clinical trials of kinase inhibitors targeting this region. By integration of small-angle X-ray scattering and nuclear magnetic resonance spectroscopy with functional studies, we show that serine 118 phosphorylation triggers an unexpected expansion of the disordered domain and disrupts specific hydrophobic clustering between two aromatic-rich regions.
View Article and Find Full Text PDFRegulation of mutant huntingtin mitochondrial toxicity by phosphomimetic mutations within its N-terminal region.
J Neurosci
January 2025
Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
Huntington's disease (HD), a neurodegenerative disease, affects approximately 30,000 people in the United States, with 200,000 more at risk. Mitochondrial dysfunction caused by mutant huntingtin (mHTT) drives early HD pathophysiology. mHTT binds the translocase of mitochondrial inner membrane (TIM23) complex, inhibiting mitochondrial protein import and altering the mitochondrial proteome.
View Article and Find Full Text PDFRas S89D mutation induced allosteric changes that promoted its nucleotide exchange and signaling activation.
Int J Biol Macromol
January 2025
Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. Electronic address:
The small GTPase Ras is among the most frequently mutated genes and its mutations often drive oncogenesis across various cancers. While the role of NRas phosphorylation at S89 in the context of a Q61R mutation in melanoma genesis remains controversial, the impact of S89 phosphorylation on NRas function has not been fully elucidated. In this study, we employed the S89D phosphorylation-mimetic mutation and demonstrated that the S89D mutation alone activated all Ras isoforms by increasing the GTP-bound population, thereby promoting ERK phosphorylation and cell proliferation.
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