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

Olga Rechkoblit, Robert E. Johnson, Angeliki Buku, Louise Prakash, Satya Prakash, Aneel K. Aggarwal

Research output: Contribution to journalArticle

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 Polδ is blocked in the replication of AraC, the lower-fidelity translesion DNA synthesis (TLS) polymerase Polη is proficient, inserting both correct and incorrect nucleotides opposite a template AraC base. Furthermore, we present high-resolution crystal structures of human Polη with a template AraC residue positioned opposite correct (G) and incorrect (A) incoming deoxynucleotides. We show that Polη 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 Polη to promote AraC induced mutagenesis in relapsed AML patients.

Original languageEnglish (US)
Article number16400
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Cytarabine
DNA-Directed DNA Polymerase
Nucleosides
Acute Myeloid Leukemia
Mutagenesis
Nucleotides
Hydrogen Bonding
Catalytic Domain
Clone Cells
Recurrence
Drug Therapy
Therapeutics

ASJC Scopus subject areas

  • General

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Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase η. / Rechkoblit, Olga; Johnson, Robert E.; Buku, Angeliki; Prakash, Louise; Prakash, Satya; Aggarwal, Aneel K.

In: Scientific reports, Vol. 9, No. 1, 16400, 01.12.2019.

Research output: Contribution to journalArticle

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