Target Coverage
- Core DNA Methylation Maintenance Readers: UHRF1 SRA domain, UHRF2 SRA domain.
- Related & Custom Targets: Plant SUVH protein SRA domains (for agricultural epigenetics), client-provided SRA constructs or disease-associated variants.
The SRA (SET and RING-associated) domain is a specialized reader module that specifically recognizes hemi-methylated CpG DNA sites, playing a central role in the maintenance of DNA methylation patterns. Its dysfunction is closely linked to aberrant epigenetic silencing in cancer. CD BioSciences offers dedicated SRA domain screening services to advance the development of inhibitors and probes that can modulate DNA methylation-dependent processes.
The SRA domain is a conserved structural module found in proteins such as UHRF1 (also known as ICBP90 or Np95) and UHRF2, which are essential regulators of DNA methylation inheritance. This domain specifically binds to hemi-methylated CpG dinucleotides—intermediate states generated during DNA replication—enabling the recruitment of DNA methyltransferase 1 (DNMT1) to ensure faithful copying of methylation patterns to daughter strands. Beyond maintenance, SRA domains are involved in linking DNA methylation to histone modification and gene silencing. Given the critical role of UHRF1 in promoting hypermethylation and silencing of tumor suppressor genes in various cancers, the SRA domain has emerged as a compelling, yet challenging, therapeutic target. High-quality screening is therefore vital to identify specific inhibitors that can disrupt this key interaction, potentially reversing pathogenic epigenetic states and offering new avenues for cancer therapy.
Fig.1 Schematic representation of the domains present in different SRA-domain containing proteins. (Mahmood N, Rabbani S A., 2017)
Leveraging deep expertise in DNA methylation biology, CD BioSciences provides a focused and technically sophisticated SRA domain screening platform designed to overcome the unique challenges of targeting DNA-protein interactions. We deliver reliable, high-quality data to support your efforts in discovering selective inhibitors and chemical probes, facilitating research into DNA methylation biology and cancer epigenetics.
We offer a comprehensive, end-to-end solution for SRA domain screening designed to address the specific challenges of targeting DNA-protein interactions. Our integrated platform streamlines the entire process, from tailored assay development to advanced data analysis, providing you with a single, reliable source for discovering modulators of this critical DNA methylation reader.
Target Coverage
Specialized Analysis Services
Application Scenarios
| Steps | Description |
|---|---|
| Consultation & Target-Specific Probe Design | We initiate the project with a detailed technical consultation to define your specific SRA domain target (e.g., UHRF1 vs. UHRF2, wild-type vs. mutant) and screening objectives. Based on this, we design and synthesize high-fidelity, biotinylated hemi-methylated DNA probes that accurately mimic the physiological substrate, ensuring assay relevance and specificity. |
| Assay Development & Biophysical Validation | Our team establishes a robust and sensitive DNA-protein interaction assay, typically utilizing a TR-FRET or AlphaScreen format. This phase involves rigorous optimization of binding buffers, protein-DNA stoichiometry, and detection parameters. We perform biophysical validation using techniques like MST to confirm the expected binding affinity (Kd) of the SRA domain for the custom probe, establishing a reliable and reproducible assay system. |
| High-Throughput Screening & Orthogonal Hit Confirmation | The validated assay is deployed for high-throughput screening of your compound library. Primary hits are identified based on statistical significance. These initial actives are immediately subjected to a secondary, orthogonal confirmation assay (e.g., a complementary EMSA format) to eliminate false positives arising from assay-specific interference, followed by full dose-response analysis to determine accurate IC₅₀ values. |
| Comprehensive Profiling & Mechanism of Action Analysis | Confirmed hits undergo in-depth characterization. This includes mandatory methylation-state specificity profiling to assess selectivity for hemi-methylated over fully methylated DNA, and optional selectivity screening against a panel of other DNA-binding domains. Data is integrated to generate a comprehensive profile for each compound, providing insights into its mechanism of action and selectivity. |
| Integrated Reporting & Translational Support | You receive a final, detailed technical report that includes all validated hit lists with chemical structures and potency data, comprehensive selectivity and specificity profiles, and expert analysis of structure-activity relationships. Furthermore, we provide strategic support for downstream translational validation, which can include designing cellular assays to test hit efficacy in reactivating silenced gene expression in relevant cancer cell models. |
In addition to the SRA domain, CD BioSciences provides comprehensive screening services for all major epigenetic reader families, including bromodomains, chromodomains, Tudor domains, MBT domains, and PHD fingers, alongside integrated multiple domains screening. Our fully customizable platform is designed to support the complete spectrum of your epigenetic research and drug discovery objectives. Contact us to learn how we can tailor our services to your specific needs.
Reference
1. Mahmood N, Rabbani S A. DNA methylation and breast cancer: mechanistic and therapeutic applications[J]. Trends Cancer Res, 2017, 12: 1-18.
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