Translesion synthesis DNA polymerases η, ι, and ν promote mutagenic replication through the anticancer nucleoside cytarabine

Jung Hoon Yoon, Jayati Roy Choudhury, Louise Prakash, Satya Prakash

Research output: Contribution to journalArticle

Abstract

Cytarabine (AraC) is the mainstay for the treatment of acute myeloid leukemia. Although complete remission is observed in a large proportion of patients, relapse occurs in almost all the cases. The chemotherapeutic action of AraC derives from its ability to inhibit DNA synthesis by the replicative polymerases (Pols); the replicative Pols can insert AraCTP at the 3' terminus of the nascent DNA strand, but they are blocked at extending synthesis from AraC. By extending synthesis from the 3'-termi-nal AraC and by replicating through AraC that becomes incorporated into DNA, translesion synthesis (TLS) DNA Pols could reduce the effectiveness of AraC in chemotherapy. Here we identify the TLS Pols required for replicating through the AraC templating residue and determine their error-proneness. We provide evidence that TLS makes a consequential contribution to the replication of AraC-damaged DNA; that TLS through AraC is conducted by three different pathways dependent upon Polη, Polι, and Polν, respectively; and that TLS by all these Pols incurs considerable mutagenesis. The prominent role of TLS in promoting proficient and mutagenic replication through AraC suggests that TLS inhibition in acute myeloid leukemia patients would increase the effectiveness of AraC chemotherapy; and by reducing mutation formation, TLS inhibition may dampen the emergence of drug-resistant tumors and thereby the high incidence of relapse in AraC-treated patients.

Original languageEnglish (US)
Pages (from-to)19048-19054
Number of pages7
JournalJournal of Biological Chemistry
Volume294
Issue number50
DOIs
StatePublished - Jan 1 2019

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Cytarabine
DNA-Directed DNA Polymerase
Nucleosides
DNA
Acute Myeloid Leukemia
Recurrence
Drug Therapy
Mutagenesis
Chemotherapy
Mutation
Incidence
Pharmaceutical Preparations
Neoplasms
Tumors
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Translesion synthesis DNA polymerases η, ι, and ν promote mutagenic replication through the anticancer nucleoside cytarabine. / Yoon, Jung Hoon; Choudhury, Jayati Roy; Prakash, Louise; Prakash, Satya.

In: Journal of Biological Chemistry, Vol. 294, No. 50, 01.01.2019, p. 19048-19054.

Research output: Contribution to journalArticle

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