TDP1 is critical for the repair of DNA breaks induced by sapacitabine, a nucleoside also targeting ATM- and BRCA-deficient tumors

Muthana Al Abo, Hiroyuki Sasanuma, Xiaojun Liu, Vinodh N. Rajapakse, Shar yin Huang, Evgeny Kiselev, Shunichi Takeda, William Plunkett, Yves Pommier

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes b-elimination that generates single-strand breaks with abnormal 30-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes nonphosphorylated 30-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1/ DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC. We also identified BRCA1, FANCD2, and PCNA in the DNA repair pathways to CNDAC. Comparing CNDAC with the chemically related arabinosyl nucleoside analog, cytosine arabinoside (cytarabine, AraC) and the topoisomerase I inhibitor camptothecin (CPT), which both generate 30-end blocking DNA lesions that are also repaired by TDP1, we found that inactivation of BRCA2 renders cells hypersensitive to CNDAC and CPT but not to AraC. By contrast, cells lacking PARP1 were only hypersensitive to CPT but not to CNDAC or AraC. Examination of TDP1 expression in the cancer cell line databases (CCLE, GDSC, NCI-60) and human cancers (TCGA) revealed a broad range of expression of TDP1, which was correlated with PARP1 expression, TDP1 gene copy number and promoter methylation. Thus, this study identifies the importance of TDP1 as a novel determinant of response to CNDAC across various cancer types (especially non–small cell lung cancers), and demonstrates the differential involvement of BRCA2, PARP1, and TDP1 in the cellular responses to CNDAC, AraC, and CPT.

Original languageEnglish (US)
Pages (from-to)2543-2551
Number of pages9
JournalMolecular cancer therapeutics
Volume16
Issue number11
DOIs
StatePublished - Nov 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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