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Updated: Jun 5, 2026

A Simple Method to Identify Kinases That Regulate Embryonic Stem Cell Pluripotency by High-throughput Inhibitor Screening
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Direct Mapping of CDK2 Substrates in Embryonic Stem Cells Uncovers an AP-Site Repair Mechanism via HMCES

Benjamin R Topacio1,2,3,4,5, Eli-Eelika Esvald4,5, Jürgen Tuvikene4

  • 1Department of Biomolecular Engineering, University of California, Santa Cruz, CA, USA.

Biorxiv : the Preprint Server for Biology
|June 4, 2026
PubMed

Insights

Embryonic stem cells (ESCs) maintain genome stability during rapid proliferation. A new CDK2-HMCES pathway links cell cycle progression to DNA repair, ensuring genomic integrity in mouse ESCs.

Area of Science:

  • Cell Biology
  • Genomics
  • Biochemistry

Background:

  • Embryonic stem cells (ESCs) exhibit rapid proliferation and maintain genomic integrity.
  • High cell-cycle kinase activity in ESCs is linked to genome stability, but the mechanisms are unclear.

Purpose of the Study:

  • To define the substrate landscape of CDK2 in mouse ESCs.
  • To investigate the role of CDK2 in regulating HMCES, a DNA repair protein.
  • To elucidate the CDK2-HMCES signaling axis in maintaining ESC genome stability.

Main Methods:

  • Engineered mouse ESCs to express an analog-sensitive CDK2.
  • Utilized thiophosphate labeling and mass spectrometry to identify CDK2 substrates.
  • Performed mutational analysis to map HMCES interactions and phosphorylation sites.

Main Results:

  • Identified 65 CDK2 substrates, including HMCES, a sensor of apurinic/apyrimidinic (AP) sites.
  • Discovered three CDK2-dependent phosphorylation sites on HMCES that reduce its ssDNA binding.
  • Demonstrated that HMCES phosphorylation by cyclin E-CDK2 promotes AP-site repair and ESC proliferation.

Conclusions:

  • Uncovered a novel CDK2-HMCES signaling axis in mouse ESCs.
  • This pathway connects rapid cell-cycle progression with genome stability maintenance.
  • HMCES phosphorylation is crucial for AP-site repair and proliferation in ESCs.

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