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Nuclear DAB2IP regulates DNA replication initiation through activating PLK1-mediated HBO1 phosphorylation

Zeng-Fu Shang1, Lan Yu2, Ciara Newman1

  • 1Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas TX 75390, United States.

Nucleic Acids Research
|November 20, 2025
PubMed

Insights

Disabled homolog 2 interacting protein (DAB2IP) promotes DNA replication initiation and maintains genome stability. Its interaction with HBO1 and phosphorylation by CDK1 are crucial for DNA replication and cellular homeostasis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Disabled homolog 2 interacting protein (DAB2IP) is a known tumor suppressor involved in cell cycle regulation.
  • Previous studies linked DAB2IP to mitosis progression via PLK1.
  • The precise role of DAB2IP in DNA replication remained unclear.

Purpose of the Study:

  • To investigate the novel function of DAB2IP in DNA replication origin firing.
  • To elucidate the molecular mechanisms underlying DAB2IP's role in DNA replication.
  • To understand how DAB2IP contributes to maintaining genome integrity.

Main Methods:

  • Nuclear localization and interaction studies of DAB2IP.
  • Analysis of HBO1 and PLK1 interactions and phosphorylation.
  • Assessment of histone H3 acetylation (H3K14Ac) and MCM complex loading.
  • Investigation of ATR and CDK1 regulation of DAB2IP phosphorylation.
  • Evaluation of genomic instability markers upon DAB2IP ablation or phosphorylation defects.

Main Results:

  • DAB2IP interacts with HBO1 in the nucleus, enhancing HBO1-PLK1 interaction and PLK1-mediated HBO1 phosphorylation.
  • HBO1-directed H3K14Ac facilitates minichromosome maintenance (MCM) complex loading onto chromatin.
  • ATR-regulated CDK1-mediated phosphorylation of DAB2IP is essential for HBO1-PLK1 complex formation and activation.
  • Loss of DAB2IP phosphorylation leads to genomic instability, incomplete DNA replication, and accumulation of ultrafine bridges and 53BP1 bodies.

Conclusions:

  • DAB2IP plays a critical role in initiating DNA replication by regulating HBO1 activity.
  • DAB2IP phosphorylation by CDK1 is vital for DNA replication and genomic stability.
  • These findings reveal a novel mechanism for DAB2IP in maintaining cellular homeostasis through DNA replication control.

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