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

Hossain, Manzar, Tramantano, Michael, Naik, Sanjay, Stillman, Bruce (October 2026) A role for CIZ1, a Nuclear Matrix Protein Overexpressed in Cancer Cells, in Controlling the Initiation of DNA Replication. bioRxiv. ISSN 2692-8205 (Submitted)

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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.

Item Type: Paper
Subjects: bioinformatics
diseases & disorders > cancer
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > matrix protein
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Stillman lab
CSHL Post Doctoral Fellows
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 13 October 2026
Date Deposited: 21 Oct 2026 17:58
Last Modified: 21 Oct 2026 17:58
Related URLs:
URI: https://repository.cshl.edu/id/eprint/42343

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