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| Status |
Public on Jun 21, 2024 |
| Title |
Synthetic essentiality of thymine DNA glycosylase in p53-deficient cancer [CUT&Tag] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| 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.
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| Overall design |
Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for TDG and p53 as well as CUT&Tag for P300 and the histone modifications H3K9me3, H3K4me3 in B16 cells.
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| Contributor(s) |
Zhou J, Shao Z |
| Citation missing |
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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
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| Department |
Center for Excellence in Molecular Cell Science
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| Street address |
Yueyang Road 320
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| City |
shanghai |
| State/province |
--- Select a state --- |
| ZIP/Postal code |
200031 |
| Country |
China |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE236728 |
Synthetic essentiality of thymine DNA glycosylase in p53-deficient cancer |
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| Relations |
| BioProject |
PRJNA992083 |
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