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bioRxiv · 10.64898/2026.10.10.758243

A role for CIZ1, a Nuclear Matrix Protein Overexpressed in Cancer Cells, in Controlling the Initiation of DNA Replication

Hossain, M.·Tramantano, M.·Naik, S.·Stillman, B.
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Abstract

DNA replication licensing is tightly coordinated with cell-cycle progression to ensure genome stability. Here we demonstrate that CIZ1, a nuclear matrix scaffold protein in human cells, coordinates DNA replication licensing through direct interactions with the Origin Recognition Complex (ORC), CDC6, and Cyclins E/A-CDK2. The C-terminal zinc finger region of CIZ1 mediates binding to the cyclin-binding motifs of ORC1 and CDC6, and Cyclin -CDK-dependent phosphorylation regulates these interactions. Cell cycle analyses demonstrated a dynamic association of CIZ1 with ORC1 and CDC6. Functional studies showed that CIZ1 depletion impaired MCM loading, reduced DNA synthesis, delayed S-phase progression and inhibited cell proliferation. Cancer cells overexpressing CIZ1 exhibited an enhanced dependency on its expression, and CRISPR tiling screens identified the C-terminal regulatory region containing cyclin-binding motifs and CDK phosphorylation sites as essential for cell proliferation. Acute degradation of CIZ1 further revealed an unexpected role in maintaining CCCTC-binding factor (CTCF) occupancy at specific genomic loci and regulating transcriptional programs associated with cell adhesion and migration, indicating that CIZ1 links DNA replication with higher-order genome organization. Finally, depletion of CIZ1 significantly suppressed colorectal tumor growth in xenograft models. Together, these findings establish CIZ1 as a multifunctional scaffold that integrates DNA replication licensing, Cyclin -CDK signaling, and chromatin architecture.

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Hossain, M., Tramantano, M., Naik, S., Stillman, B.. 2026-10-13. A role for CIZ1, a Nuclear Matrix Protein Overexpressed in Cancer Cells, in Controlling the Initiation of DNA Replication. https://doi.org/10.64898/2026.10.10.758243

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