Reduced Maintenance DNA Methylation Thresholds Enable Sensitive Reporter Assays for UHRF1 and DNMT1 Inhibition - PubMed
5 hours ago
- #Drug Discovery
- #Epigenetic Therapy
- #DNA Methylation
- Aberrant DNA methylation silences tumor suppressor genes and is maintained by the UHRF1-DNMT1 axis, making it a target for hypomethylating agents.
- Reversing DNA methylation abnormalities requires lowering DNMT1 below a stringent threshold, which also applies to UHRF1, posing challenges for drug discovery.
- Reducing genetic redundancy in DNMT1 or UHRF1 lowers these thresholds and sensitizes cells to inhibition, enabling sensitive reporter assays for monitoring TSG reactivation.
- Engineered recombinant reporter systems in hypomorphic cells improve sensitivity and dynamic range for high-throughput screening of DNMT1 and UHRF1 inhibitors.
- These platforms facilitate optimization of timing and combination strategies with other epigenetic agents to maximize tumor suppressor gene re-expression.