Finding. Nucleotide-excision-repair-deficient cancers die when they lose the mitochondrial iron carrier SLC25A28. Yang, Lipkin and colleagues delete ERCC4 in RT112/84 bladder-cancer cells, confirm NER failure with a host-cell reactivation assay, and run a genome-wide CRISPR screen against the isogenic wild type. SLC25A28 ranks first. DepMap agrees. Clonogenic assays extend the lethal to ERCC2, ERCC3, ERCC4 and ERCC5. An inducible knockout slows ERCC4-deficient xenografts. RNA-seq after SLC25A28 loss fills with reactive-oxygen and DNA-damage programs, and measured intracellular ROS goes up. The authors' translational sentence is the point: this is a way at the ~10% of bladder, upper-tract, and endometrial tumors with somatic NER loss that does not start with platinum.
Why this paper matters
Platinum works in NER-deficient tumors and wrecks kidneys. A mitochondrial iron transporter as a synthetic-lethal target is a different product class: metabolic oxidative stress that only the repair-poor cell cannot tolerate. SLC25A28 is mitoferrin-2. Putting a named mitochondrial carrier on a DNA-repair genotype is the mitochondrial news.
Keep the mechanism at the volume they use. They measured ROS and a stress transcriptome. They did not, in the abstract, measure mitochondrial iron flux or Fe-S clusters. The implication is still mitochondrial iron homeostasis as a NER-independent dependency.
What they actually measured
Isogenic CRISPR screen, four NER genes in clonogenics, xenograft, GSEA, ROS. Functional NER loss is not assumed; it is assayed.
How to read the score
Low 90s. Named mitochondrial transporter, genotype-restricted lethal, in vivo, ROS. Confidence is high for the genetic interaction in this line. There is no drug.
Caveats
No inhibitor. One bladder background. Endometrial and upper-tract numbers are epidemiology. Do not treat iron chelation as a proven substitute.
What to do with it
If you score NER-mutant bladder, add SLC25A28 CRISPR or a mitoferrin readout. If you develop mitochondrial-iron tools, this is the synthetic-lethal indication to test. Do not drop cisplatin from a protocol because of this brief.