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Open AccessArticle

DNA Damage-Response Pathway Heterogeneity of Human Lung Cancer A549 and H1299 Cells Determines Sensitivity to 8-Chloro-Adenosine

1
Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
2
Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Science, Peking University Health Science Center, Beijing 100191, China
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(6), 1587; https://doi.org/10.3390/ijms19061587
Received: 6 April 2018 / Revised: 10 May 2018 / Accepted: 21 May 2018 / Published: 28 May 2018
(This article belongs to the Special Issue DNA Replication Stress)
Human lung cancer H1299 (p53-null) cells often display enhanced susceptibility to chemotherapeutics comparing to A549 (p53-wt) cells. However, little is known regarding to the association of DNA damage-response (DDR) pathway heterogeneity with drug sensitivity in these two cells. We investigated the DDR pathway differences between A549 and H1299 cells exposed to 8-chloro-adenosine (8-Cl-Ado), a potential anticancer drug that can induce DNA double-strand breaks (DSBs), and found that the hypersensitivity of H1299 cells to 8-Cl-Ado is associated with its DSB overaccumulation. The major causes of excessive DSBs in H1299 cells are as follows: First, defect of p53-p21 signal and phosphorylation of SMC1 increase S phase cells, where replication of DNA containing single-strand DNA break (SSB) produces more DSBs in H1299 cells. Second, p53 defect and no available induction of DNA repair protein p53R2 impair DNA repair activity in H1299 cells more severely than A549 cells. Third, cleavage of PARP-1 inhibits topoisomerase I and/or topoisomerase I-like activity of PARP-1, aggravates DNA DSBs and DNA repair mechanism impairment in H1299 cells. Together, DDR pathway heterogeneity of cancer cells is linked to cancer susceptibility to DNA damage-based chemotherapeutics, which may provide aid in design of chemotherapy strategy to improve treatment outcomes. View Full-Text
Keywords: A549 cells; H1299 cells; heterogeneity; DNA damage response; 8-chloro-adenosine A549 cells; H1299 cells; heterogeneity; DNA damage response; 8-chloro-adenosine
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Yang, S.-Y.; Li, Y.; An, G.-S.; Ni, J.-H.; Jia, H.-T.; Li, S.-Y. DNA Damage-Response Pathway Heterogeneity of Human Lung Cancer A549 and H1299 Cells Determines Sensitivity to 8-Chloro-Adenosine. Int. J. Mol. Sci. 2018, 19, 1587.

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