Structural basis for polymerase η–promoted resistance to the anticancer nucleoside analog cytarabine

Olga Rechkoblit, Jayati Roy Choudhury, Angeliki Buku, Louise Prakash, Satya Prakash, Aneel K. Aggarwal

Research output: Contribution to journalArticle

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Abstract

Cytarabine (AraC) is an essential chemotherapeutic for acute myeloid leukemia (AML) and resistance to this drug is a major cause of treatment failure. AraC is a nucleoside analog that differs from 2′-deoxycytidine only by the presence of an additional hydroxyl group at the C2′ position of the 2′-deoxyribose. The active form of the drug AraC 5′-triphosphate (AraCTP) is utilized by human replicative DNA polymerases to insert AraC at the 3′ terminus of a growing DNA chain. This impedes further primer extension and is a primary basis for the drug action. The Y-family translesion synthesis (TLS) DNA polymerase η (Polη) counteracts this barrier to DNA replication by efficient extension from AraC-terminated primers. Here, we provide high-resolution structures of human Polη with AraC incorporated at the 3′-primer terminus. We show that Polη can accommodate AraC at different stages of the catalytic cycle, and that it can manipulate the conformation of the AraC sugar via specific hydrogen bonding and stacking interactions. Taken together, the structures provide a basis for the ability of Polη to extend DNA synthesis from AraC terminated primers.

Original languageEnglish (US)
Article number12702
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Cytarabine
Nucleosides
DNA-Directed DNA Polymerase
DNA
Pharmaceutical Preparations
Deoxyribose
Deoxycytidine
Sugars
Hydroxyl Radical
Conformations
Hydrogen bonds

ASJC Scopus subject areas

  • General

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Structural basis for polymerase η–promoted resistance to the anticancer nucleoside analog cytarabine. / Rechkoblit, Olga; Choudhury, Jayati Roy; Buku, Angeliki; Prakash, Louise; Prakash, Satya; Aggarwal, Aneel K.

In: Scientific Reports, Vol. 8, No. 1, 12702, 01.12.2018.

Research output: Contribution to journalArticle

Rechkoblit, Olga ; Choudhury, Jayati Roy ; Buku, Angeliki ; Prakash, Louise ; Prakash, Satya ; Aggarwal, Aneel K. / Structural basis for polymerase η–promoted resistance to the anticancer nucleoside analog cytarabine. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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