A TRIM28-MCM7 regulatory axis sustains DNA replication programs in glioblastoma

Aberrant activation of DNA replication programs is essential for Glioblastoma cell proliferation, but the upstream mechanisms that maintain replication competence remain poorly defined. Here, we identify TRIM28 as a multilayered regulator of DNA replication in Glioblastoma. TRIM28 was highly expressed in Glioblastoma tissues, increased with tumor grade, and predicted poor prognosis. The enrichment analysis linked TRIM28-high tumors to DNA replication-related pathways, and TRIM28 depletion impaired BrdU incorporation and CldU-labeled replication activity in Glioblastoma cells. Integrated analyses of Glioblastoma datasets identified MCM7, a core component of the MCM2-7 replicative helicase complex, as a TRIM28-associated replication factor. MCM7 was upregulated in Glioblastoma, positively correlated with TRIM28, and associated with unfavorable clinical outcome. Mechanistically, TRIM28 occupied the MCM7 promoter and enhanced its transcriptional activity, as supported by public ChIP-seq data, promoter reporter assays, and ChIP-qPCR validation. In parallel, TRIM28 interacted with MCM7 and promoted its K63-dependent ubiquitination. These findings reveal a TRIM28-MCM7 axis that supports DNA replication-associated proliferation through transcriptional activation and K63-dependent post-translational regulation.