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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Cancer Biology and Translational Studies

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 and Yves Pommier
Muthana Al Abo
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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Hiroyuki Sasanuma
Department of Radiation Genetics, Kyoto University, Graduate School of Medicine, Yoshida Konoe, Sakyo-ku, Kyoto, Japan.
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Xiaojun Liu
Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
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Vinodh N. Rajapakse
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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Shar-yin Huang
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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Evgeny Kiselev
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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Shunichi Takeda
Department of Radiation Genetics, Kyoto University, Graduate School of Medicine, Yoshida Konoe, Sakyo-ku, Kyoto, Japan.
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William Plunkett
Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
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Yves Pommier
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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  • For correspondence: pommier@nih.gov
DOI: 10.1158/1535-7163.MCT-17-0110 Published November 2017
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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 β-elimination that generates single-strand breaks with abnormal 3′-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes nonphosphorylated 3′-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 3′-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. Mol Cancer Ther; 16(11); 2543–51. ©2017 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received February 1, 2017.
  • Revision received May 24, 2017.
  • Accepted July 27, 2017.
  • ©2017 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 16 (11)
November 2017
Volume 16, Issue 11
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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 and Yves Pommier
Mol Cancer Ther November 1 2017 (16) (11) 2543-2551; DOI: 10.1158/1535-7163.MCT-17-0110

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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 and Yves Pommier
Mol Cancer Ther November 1 2017 (16) (11) 2543-2551; DOI: 10.1158/1535-7163.MCT-17-0110
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Molecular Cancer Therapeutics
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