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Updated: Mar 17, 2026
A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Novel synthetic lethality screening method identifies TIP60-dependent radiation sensitivity in the absence of BAF180
Suzanna R Hopkins1, Grant A McGregor1, Johanne M Murray1
1Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 RQ9, United Kingdom.
Abstract:
In recent years, research into synthetic lethality and how it can be exploited in cancer treatments has emerged as major focus in cancer research. However, the lack of a simple to use, sensitive and standardised assay to test for synthetic interactions has been slowing the efforts. Here we present a novel approach to synthetic lethality screening based on co-culturing two syngeneic cell lines containing individual fluorescent tags. By associating shRNAs for a target gene or control to individual fluorescence labels, we can easily follow individual cell fates upon siRNA treatment and high content imaging. We have demonstrated that the system can recapitulate the functional defects of the target gene depletion and is capable of discovering novel synthetic interactors and phenotypes. In a trial screen, we show that TIP60 exhibits synthetic lethality interaction with BAF180, and that in the absence of TIP60, there is an increase micronuclei dependent on the level of BAF180 loss, significantly above levels seen with BAF180 present. Moreover, the severity of the interactions correlates with proxy measurements of BAF180 knockdown efficacy, which may expand its usefulness to addressing synthetic interactions through titratable hypomorphic gene expression.
Insights
This study introduces a novel assay for screening synthetic lethality in cancer research. The new method identifies interactions, such as TIP60 and BAF180, revealing potential new therapeutic targets.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Synthetic lethality is a key strategy in cancer therapy, but screening for these interactions is challenging.
- Existing assays lack simplicity, sensitivity, and standardization, hindering progress in identifying synthetic lethal pairs.
Purpose of the Study:
- To develop and validate a novel, user-friendly assay for high-throughput screening of synthetic lethal interactions.
- To demonstrate the assay's capability in identifying known and novel synthetic lethal relationships and associated phenotypes.
Main Methods:
- Co-culturing of two syngeneic cell lines, each with a unique fluorescent tag.
- Association of short hairpin RNAs (shRNAs) targeting specific genes or controls with fluorescence labels.
- High-content imaging and analysis to track individual cell fates post-siRNA treatment.
Main Results:
- The assay successfully recapitulated known functional defects upon gene depletion.
- A novel synthetic lethality interaction between TIP60 and BAF180 was identified.
- Increased micronuclei formation was observed in TIP60-depleted cells, dependent on BAF180 levels, indicating a specific synthetic lethal phenotype.
Conclusions:
- The developed co-culture fluorescent tagging assay is a sensitive and effective tool for synthetic lethality screening.
- This assay can identify novel synthetic lethal interactions and phenotypes, advancing cancer therapeutic research.
- The findings highlight the synthetic lethality between TIP60 and BAF180, with potential implications for targeted cancer therapies.
