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Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase ?.

ABSTRACT: Cytarabine (AraC) is the mainstay chemotherapy for acute myeloid leukemia (AML). Whereas initial treatment with AraC is usually successful, most AML patients tend to relapse, and AraC treatment-induced mutagenesis may contribute to the development of chemo-resistant leukemic clones. We show here that whereas the high-fidelity replicative polymerase Pol? is blocked in the replication of AraC, the lower-fidelity translesion DNA synthesis (TLS) polymerase Pol? is proficient, inserting both correct and incorrect nucleotides opposite a template AraC base. Furthermore, we present high-resolution crystal structures of human Pol? with a template AraC residue positioned opposite correct (G) and incorrect (A) incoming deoxynucleotides. We show that Pol? can accommodate local perturbation caused by the AraC via specific hydrogen bonding and maintain a reaction-ready active site alignment for insertion of both correct and incorrect incoming nucleotides. Taken together, the structures provide a novel basis for the ability of Pol? to promote AraC induced mutagenesis in relapsed AML patients.

SUBMITTER: Rechkoblit O

PROVIDER: S-EPMC6841716 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Structural basis for polymerase ?-promoted resistance to the anticancer nucleoside analog cytarabine.

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