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Direct Mapping of CDK2 Substrates in Embryonic Stem Cells Uncovers an AP-Site Repair Mechanism via HMCES Phosphorylation

Topacio, B. R.; Esvald, E.-E.; Tuvikene, J.; Langroudi, L.; Maity, T. K.; Jenkins, L. M.; Stracker, T. H.; Koivomägi, M.; Shariati, S. A.

2026-05-20 developmental biology
10.64898/2026.05.18.726044 bioRxiv
Show abstract

Embryonic stem cells (ESCs) proliferate rapidly while robustly maintaining genomic integrity and exhibiting high cell-cycle kinase activity. How this activity contributes to genome integrity remains unclear. Here, using mouse ESCs engineered to express an analog-sensitive CDK2, we combine thiophosphate labeling with mass spectrometry to define a high-confidence CDK2 substrate landscape. We uncovered 65 CDK2 substrates in total, including both known and previously unrecognized substrates. Among these, HMCES, a sensor of apurinic/apyrimidinic (AP) sites, was identified as a specific cyclin E-CDK2 substrate. We mapped three CDK2-dependent phosphorylation sites in HMCES and showed that phosphorylation of these sites decreased HMCES binding to ssDNA. Mutational analysis further revealed that HMCES docks to cyclin E-CDK2 complexes via the hydrophobic patch on cyclin E. Finally, we demonstrated that HMCES phosphorylation contributes to AP-site repair and promotes ESC proliferation. Together, our findings uncover a CDK2-HMCES signaling axis that links rapid cell-cycle progression to the preservation of genome stability in mouse ESCs.

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