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Series GSE236727 Query DataSets for GSE236727
Status Public on Jun 21, 2024
Title Synthetic essentiality of thymine DNA glycosylase in p53-deficient cancer [scRNA-seq]
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Thymine DNA Glycosylase (TDG) is a versatile protein involved in DNA mismatch repair, DNA demethylation, and transcriptional regulation. Here, we identify TDG as a synthetic essential effector in p53-deficient tumours. We found that deletion of TDG inhibits cell proliferation specifically in p53-deficient cancer cells. Using a genetically engineered mouse model of lung adenocarcinoma (LUAD), we demonstrate that depletion of TDG suppresses tumour growth in the p53-deficient context. Notably, A novel and selective inhibitor developed to disrupt the DNA binding activity of TDG exhibits therapeutic efficacy against p53-deficient tumours in both cellular and xenograft models. Mechanistically, TDG coordinates with p53 to orchestrate the transcription of RNA helicase DHX9, which functions to eliminate dsRNA. Depletion of TDG in p53-deficient cells results in the downregulation of DHX9 and aberrant cytoplasmic double-strand (dsRNA) accumulation derived from Alu elements, subsequently activating the RIG-I/MDA5-MAVS mediated antiviral response. Moreover, single-cell RNA-sequencing analysis revealed the depletion of TDG in p53-deficient tumours facilitates the recruitment of tumour-infiltrating lymphocytes. We observed that TDG inhibition combined with immune checkpoint blockade (ICB) achieved a strong synergistic anti-tumour effect in p53-deficient tumours. This study highlights the function of TDG in maintaining p53-deficient tumour growth and provides an alternative therapeutic target for p53-deficient cancers.
 
Overall design We used single cell RNA sequencing (scRNA-seq) to analyze the tumour-infiltrating lymphocytes in subcutaneous KP tumours
 
Contributor(s) Zhou J, Yu Y
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Submission date Jul 06, 2023
Last update date Jun 22, 2024
Contact name Zhenyu Shao
Organization name Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Department Center for Excellence in Molecular Cell Science
Street address Yueyang Road 320
City shanghai
State/province --- Select a state ---
ZIP/Postal code 200031
Country China
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (2)
GSM7574585 KP scRNA-Seq
GSM7574586 KPT scRNA-Seq
This SubSeries is part of SuperSeries:
GSE236728 Synthetic essentiality of thymine DNA glycosylase in p53-deficient cancer
Relations
BioProject PRJNA992209

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Supplementary file Size Download File type/resource
GSE236727_RAW.tar 87.5 Mb (http)(custom) TAR (of MTX, TSV)
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Raw data are available in SRA
Processed data provided as supplementary file

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