SLD5/GINS4 controls dynein-dependent centrosome maturation and exposes a candidate mitotic vulnerability in cancer

Faithful proliferation requires coordinated DNA replication with centrosome maturation and spindle-pole integrity. SLD5, encoded by GINS4, is a core component of the GINS replication complex and is frequently elevated in tumors, but whether it links replication-associated cancer states to centrosome control has remained unclear. Here, we show that GINS4/SLD5 is recurrently upregulated across human cancers at transcript and protein levels and marks tumor programs enriched for DNA replication, chromosome segregation, and mitotic control. In cancer cells, Sld5 depletion dispersed PCM1, AZI1, and CEP290-positive centriolar satellites without eliminating these satellite proteins, reduced dynein heavy chain expression, and destabilized dynein-dynactin localization at spindle poles. Direct depletion of dynein heavy chain, co-depletion analyses, and pharmacological inhibition of dynein motor activity with ciliobrevin D phenocopied Sld5 loss, causing satellite dispersion, defective recruitment of PLK1, Aurora A, CEP192, and CEP215 to centrosomes, and multipolar spindle formation. These defects occurred without detectable DNA damage or checkpoint activation, indicating a non-canonical Sld5 function beyond its role in the replisome. Cancer dependency and kinase network analyses further nominate SLD5-associated mitotic and checkpoint pathways as therapeutic targets. Our findings identify SLD5/GINS4 as a regulator of dynein-dependent centrosome maturation and a candidate vulnerability in replication-driven cancers, with potential value for biomarker-guided therapeutic stratification.