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The antitumor toxin CD437 is a direct inhibitor of DNA polymerase α

2016; Nature Portfolio; Volume: 12; Issue: 7 Linguagem: Inglês

10.1038/nchembio.2082

1552-4469

Ting Han, Maria Goralski, Emanuela Capota, Shae B. Padrick, Jiwoong Kim, Yang Xie, Deepak Nijhawan,

Cancer therapeutics and mechanisms

A forward-genetic screen revealed that the mutations in DNA polymerase α (POLA1) are resistant to the effects of CD437. The direct interaction of CD437 and POLA1 blocks DNA replication and promotes cancer cell death. CD437 is a retinoid-like small molecule that selectively induces apoptosis in cancer cells, but not in normal cells, through an unknown mechanism. We used a forward-genetic strategy to discover mutations in POLA1 that coincide with CD437 resistance (POLA1R). Introduction of one of these mutations into cancer cells by CRISPR-Cas9 genome editing conferred CD437 resistance, demonstrating causality. POLA1 encodes DNA polymerase α, the enzyme responsible for initiating DNA synthesis during the S phase of the cell cycle. CD437 inhibits DNA replication in cells and recombinant POLA1 activity in vitro. Both effects are abrogated by the identified POLA1 mutations, supporting POLA1 as the direct antitumor target of CD437. In addition, we detected an increase in the total fluorescence intensity and anisotropy of CD437 in the presence of increasing concentrations of POLA1 that is consistent with a direct binding interaction. The discovery of POLA1 as the direct anticancer target for CD437 has the potential to catalyze the development of CD437 into an anticancer therapeutic.