title: The antitumor toxin CD437 is a direct inhibitor of DNA polymerase α.
abstract: 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 (POLA1(R)). 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.
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Goralski
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Capota
authors.affiliation: Department of Biophysics, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Shae B
authors.initials: SB
authors.lastname: Padrick
authors.affiliation: Quantitative Biomedical Research Center, Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, Texas, USA.|Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jiwoong
authors.initials: J
authors.lastname: Kim
authors.affiliation: Quantitative Biomedical Research Center, Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, Texas, USA.|Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.|Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.|Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Nijhawan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C099555:CD 437; D004791:Enzyme Inhibitors; D012176:Retinoids; D004256:DNA Polymerase I