Histone lysine methyltransferase SUV420H1, which is responsible for site-specific di-/tri-methylation of histone H4 lysine 20 (H4K20), has crucial roles in DNA-templated processes, including DNA replication, DNA damage repair, and chromatin compaction. Its mutations frequently occur in human cancers. Nucleosomes containing the histone variant H2A.Z enhance the catalytic activities of SUV420H1 on H4K20 di-methylation deposition, regulating early replication origins. However, the molecular mechanism by which SUV420H1 specifically recognizes and deposits H4K20 methyl marks on nucleosomes remains poorly understood. Here we report the cryo-electron microscopy structures of SUV420H1 associated with H2A-containing nucleosome core particles (NCPs), and H2A.Z-containing NCPs. We find that SUV420H1 makes extensive site-specific contacts with histone and DNA regions. SUV420H1 C-terminal domain recognizes the H2A-H2B acidic patch of NCPs through its two arginine anchors, thus enabling H4K20 insertion for catalysis specifically. We also identify important residues increasing the catalytic activities of SUV420H1 bound to H2A.Z NCPs. In vitro and in vivo functional analyses reveal that multiple disease-associated mutations at the interfaces are essential for its catalytic activity and chromatin state regulation. Together, our study provides molecular insights into the nucleosome-based recognition and methylation mechanisms of SUV420H1, and a structural basis for understanding SUV420H1-related human disease.
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http://dx.doi.org/10.1038/s41421-023-00620-5 | DOI Listing |
Brain Commun
September 2024
Department of Anesthesiology and Perioperative Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan University People's Hospital, Zhengzhou, Henan 450003, China.
Early childhood exposure to general anaesthesia has been linked to potential changes in infant brain morphology and behaviour in preclinical studies, contributing to long-term behaviours associated with autism spectrum disorder. This study investigates the association between early childhood exposure to general anaesthesia and the risk of autism, using a population-based cohort study with matching for baseline characteristics and evaluates the effect of sevoflurane exposure on autism-like behaviour in mice, using the Taiwan Maternal and Child Health Database. Children aged 0-3 who received at least one exposure to general anaesthesia between 2004 and 2014 were matched 1:1 with children who were not exposed.
View Article and Find Full Text PDFDNA double-strand breaks (DSBs) are highly toxic lesions that underly the efficacy of ionizing radiation (IR) and a large number of cytotoxic chemotherapies . Yet, abnormal repair of DSBs is associated with genomic instability and may contribute to cancer heterogeneity and tumour evolution. Here, we show that DSBs induced by IR, by DSB-inducing chemotherapeutics, or by the expression of a rare-cutting restriction endonuclease induce large-scale genomic amplification in human cancer cells.
View Article and Find Full Text PDFSTAR Protoc
September 2024
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:
The histone lysine methyltransferase SUV420H1 preferentially targets the H2A.Z-containing nucleosome core particle (H2A.Z-NCP) and catalyzes the H4K20me2 modification at replication origins.
View Article and Find Full Text PDFiScience
February 2024
Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
A long CGG-repeat tract in the gene induces the epigenetic silencing that causes fragile X syndrome (FXS). Epigenetic changes include H4K20 trimethylation, a heterochromatic modification frequently implicated in transcriptional silencing. Here, we report that treatment with A-196, an inhibitor of SUV420H1/H2, the enzymes responsible for H4K20 di-/trimethylation, does not affect transcription, but does result in increased chromosomal duplications.
View Article and Find Full Text PDFCancer Sci
February 2024
Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan.
Hepatocellular carcinoma (HCC) has a high rate of recurrence and poor prognosis, even after curative surgery. Multikinase inhibitors have been applied for HCC patients, but their effect has been restricted. This study aims to clarify the clinical impact of SUV420H1/KMT5B, one of the methyltransferases for histone H4 at lysine 20, and elucidate the novel mechanisms of HCC progression.
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