6-Thioguanine damages mitochondrial DNA and causes mitochondrial dysfunction in human cells

被引：22

作者：

Daehn, Ilse ^{[1
]}

Brem, Reto ^{[1
]}

Barkauskaite, Eva ^{[1
]}

Karran, Peter ^{[1
]}

机构：

[1] Clare Hall Labs, Canc Res UK London Res Inst, S Mimms EN6 3LD, Herts, England

来源：

FEBS LETTERS | 2011年 / 585卷 / 24期

关键词：

Thiopurine; Ultraviolet A; Mitochondrial DNA; Mitochondrial DNA replication; Mitochondrial DNA transcription; DNA oxidation damage; Oxidative metabolism; INFLAMMATORY-BOWEL-DISEASE; OXIDATIVE STRESS; AZATHIOPRINE; REPAIR; 6-MERCAPTOPURINE; THIOPURINES; HYPERPLASIA; THERAPY; LESIONS; MTDNA;

D O I：

10.1016/j.febslet.2011.10.040

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The anticancer and immunosuppressant thiopurines cause 6-thioguanine (6-TG) to accumulate in nuclear DNA. We report that 6-TG is also readily incorporated into mitochondrial DNA (mtDNA) where it is rapidly oxidized. The oxidized forms of mtDNA 6-TG inhibit replication by DNA Pol-gamma. Accumulation of oxidized 6-TG is associated with reduced mtDNA transcription, a decline in mitochondrial protein levels, and loss of mitochondrial function. Ultraviolet A radiation (UVA) also oxidizes mtDNA 6-TG. Cells without mtDNA are less sensitive to killing by a combination of 6-TG and UVA than their mtDNA-containing counterparts, indicating that photochemical mtDNA 6-TG oxidation contributes to 6-TG-mediated UVA photosensitization. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

引用

页码：3941 / 3946

页数：6

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