Mapping of DNA methylation-sensitive cellular processes in gingival fibroblasts using the DNMT inhibitor decitabine
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ABSTRACT:
PROVIDER: PRJNA895338 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22077259_1.fastq.gz | Fastqsanger.gz | |||
| SRR22077259_2.fastq.gz | Fastqsanger.gz | |||
| SRR22077260_1.fastq.gz | Fastqsanger.gz | |||
| SRR22077260_2.fastq.gz | Fastqsanger.gz | |||
| SRR22077261_1.fastq.gz | Fastqsanger.gz |
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Project description:Decitabine and Azacytidine are considered as epigenetic drugs that induce DNA-methyltransferase (DNMT)-DNA crosslinks, resulting in DNA-hypomethylation and -damage. Although they are already applied against myeloid cancers, important aspects of their mode of action remain unknown, highly limiting their clinical potential. Using a combinatorial approach, we reveal that the efficacy profile of both compounds primarily depends on the level of induced DNA-damage. Under low DNMT-activity, only Decitabine has a substantial impact. Conversely, when DNMT-activity is high, toxicity and cellular response to both compounds are dramatically increased, but do not primarily depend on DNA-hypomethylation or RNA-associated processes. By investigating proteome dynamics on chromatin, we show that Decitabine induces a strictly DNMT-dependent multifaceted DNA-damage response based on chromatin-recruitment, but not expression level changes of repair-associated proteins. The choice of DNA-repair pathway herby depends on the severity of Decitabine-induced DNA-lesions. While under moderate DNMT-activity, mismatch (MMR), base-excision (BER) and Fanconi anemia-dependent DNA-repair combined with homologous recombination are activated in response to Decitabine, high DNMT-activity and therefore immense replication stress, induce activation of MMR and BER followed by non-homologous end-joining.
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Project description:Decitabine (DAC), a DNA methyltransferase (DNMT) inhibitor, is tested in combination with conventional anticancer drugs as a treatment option for various solid tumors.
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