Epigenetic and genetic inactivation of tyrosyl-DNA-phosphodiesterase 1 (TDP1) in human lung cancer cells from the NCI-60 panel

DNA Repair
Rui GaoY Pommier

Abstract

Tyrosyl-DNA-phosphodiesterase 1 (TDP1) repairs 3'-blocking DNA lesions by catalytically hydrolyzing the tyrosyl-DNA-phosphodiester bond of trapped topoisomerase I (Top1) cleavage complexes (Top1cc). It also removes 3'-blocking residues derived from oxidative damage or incorporation of chain terminating anticancer and antiviral nucleosides. Thus, TDP1 is regarded as a determinant of resistance to Top1 inhibitors and chain terminating nucleosides, and possibly of genomic stability. In the 60 cell lines of the NCI Developmental Therapeutic Anticancer Screen (the NCI-60), whose whole genome transcriptome and mutations have recently been characterized, we discovered two human lung cancer cell lines deficient for TDP1 (NCI_H522 and HOP_62). HOP_62 shows undetectable TDP1 mRNA and NCI_H522 bears a homozygous deleterious mutation of TDP1 at a highly conserved amino acid residue (K292E). Absence of TDP1 protein and lack of TDP1 catalytic activity were demonstrated in cell lysates from both cell lines. Lack of TDP1 expression in HOP_62 was shown to be due to TDP1 promoter hypermethylation. Our study provides insights into the possible inactivation of TDP1 in cancers and its relationship to cellular response to Top1-targeted drugs. It als...Continue Reading

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Citations

May 27, 2014·DNA Repair·Yves PommierChristophe Marchand
Oct 22, 2014·Proceedings of the National Academy of Sciences of the United States of America·DongYu GuoHoward A Nash
Jul 18, 2014·PloS One·William C ReinholdYves Pommier
Nov 26, 2015·Science Advances·Kohei TadaAkifumi Takaori-Kondo
May 19, 2019·Cellular and Molecular Life Sciences : CMLS·Benjamin M Lorton, David Shechter
Oct 11, 2017·Scientific Reports·Yoko TakiuchiAkifumi Takaori-Kondo
Jan 11, 2020·Cell & Bioscience·Huimin ZhangJunjie Chen
Jul 16, 2014·Molecular Cancer Therapeutics·Christophe MarchandYves Pommier
Feb 10, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Chao MeiZhao-Qian Liu

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