Advances in Biology & Earth Sciences

Background: SJG-136 (NSC-694501) is a sequence-selective pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer that forms interstrand DNA crosslinks and has entered early-phase clinical trials. The genome-wide transcriptional response to SJG-136 in leukemia cells has not been fully characterized. Methods: Human K562 cells were exposed to 50 nM SJG-136 for 2, 6, 9 or 12 hours and profiled on GE Healthcare CodeLink™ Human Whole Genome Bioarrays. Differential gene expression was assessed using statistical analysis with Benjamini-Hochberg false discovery rate (FDR) correction in combination with fold-change thresholds. Gene Ontology (GO) over-representation analysis was used to summarize pathway-level responses across time. RT-PCR was used to evaluate ERCC1 expression, whereas additional DNA damage-associated genes were evaluated at the microarray transcriptomic level. Results: No significant transcriptional changes were detected at 2 h. In contrast, extensive gene modulation was observed at 6, 9 and 12 h, with approximately 1,900-3,800 transcripts altered. GO analysis revealed enrichment of pathways related to nucleotide excision repair, homologous recombination, cell-cycle checkpoint control, chromatin organization and stress response. ERCC1 expression remained constitutive and was not transcriptionally induced following SJG-136 exposure. Conclusions: SJG-136 triggers time-dependent transcriptional programs consistent with its DNA crosslinking activity, highlighting coordinated transcriptional modulation of DNA repair and regulatory pathways and supporting the rational design of combination strategies with DNA repair inhibitors.