DNA polymerase alpha-primase complex interface with Minichromosome maintenance protein 10 (MCM10) and WD repeat and HMG-box DNA-binding protein 1 (WDHD1) (Pol alpha-MCM10-WDHD1 interface)

The DNA polymerase alpha-primase complex interface with Minichromosome maintenance protein 10 (MCM10) and WD repeat and HMG-box DNA-binding protein 1 (WDHD1) is a critical regulatory junction within the eukaryotic replisome (Villa et al., 2014, Nature). This interface is essential for the recruitment and stabilization of the Pol alpha-primase complex at the replication fork, where it initiates DNA synthesis by producing RNA-DNA primers (Ricke and Bielinsky, 2004, J Biol Chem). WDHD1 (also known as CTF4) acts as a structural hub that couples the CMG helicase to Pol alpha, while MCM10 is required for helicase activation and the coordination of polymerase activity (Zhu et al., 2007, J Biol Chem). In many human cancers, such as breast and lung carcinoma, these proteins are overexpressed to facilitate rapid cell division, making the interface a promising target for anti-proliferative therapies (Baxley and Bielinsky, 2017, Genes). Disrupting these protein-protein interactions (PPIs) can trigger replication stress, DNA damage, and apoptosis, specifically in cells with high replication demands. Although no drugs targeting this specific interface are currently FDA-approved, research into small-molecule inhibitors and peptidomimetics is ongoing to exploit this vulnerability in oncology.

Other names

Pol alpha-MCM10-CTF4 interfaceDNA polymerase alpha-primase/MCM10/WDHD1 complexPol alpha-primase recruitment interfaceCTF4-Pol alpha-MCM10 interaction site

Inhibition of protein-protein interaction (PPI) to disrupt the recruitment of DNA polymerase alpha to the replication fork, preventing primer synthesis and inducing replication stress.