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

Ilse Daehn; Reto Brem; Eva Barkauskaite; Peter Karran

doi:10.1016/j.febslet.2011.10.040

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

Ilse Daehn
, Reto Brem
, Eva Barkauskaite
, Peter Karran

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

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-γ. 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.

Original language	English
Pages (from-to)	3941-3946
Number of pages	6
Journal	FEBS Letters
Volume	585
Issue number	24
DOIs	https://doi.org/10.1016/j.febslet.2011.10.040
State	Published - 15 Dec 2011

Keywords

DNA oxidation damage
Mitochondrial DNA
Mitochondrial DNA replication
Mitochondrial DNA transcription
Oxidative metabolism
Thiopurine
Ultraviolet A

Access to Document

10.1016/j.febslet.2011.10.040

Cite this

@article{93fcdb4f3f694cfa9cbdccfb9b578b2c,

title = "6-Thioguanine damages mitochondrial DNA and causes mitochondrial dysfunction in human cells",

abstract = "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-γ. 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.",

keywords = "DNA oxidation damage, Mitochondrial DNA, Mitochondrial DNA replication, Mitochondrial DNA transcription, Oxidative metabolism, Thiopurine, Ultraviolet A",

author = "Ilse Daehn and Reto Brem and Eva Barkauskaite and Peter Karran",

note = "Funding Information: We are grateful to Dr. Bill Copeland for kindly providing DNA pol-γ. This work was supported by Cancer Research UK. ",

year = "2011",

month = dec,

day = "15",

doi = "10.1016/j.febslet.2011.10.040",

language = "English",

volume = "585",

pages = "3941--3946",

journal = "FEBS Letters",

issn = "0014-5793",

publisher = "John Wiley and Sons Inc.",

number = "24",

}

TY - JOUR

T1 - 6-Thioguanine damages mitochondrial DNA and causes mitochondrial dysfunction in human cells

AU - Daehn, Ilse

AU - Brem, Reto

AU - Barkauskaite, Eva

AU - Karran, Peter

N1 - Funding Information: We are grateful to Dr. Bill Copeland for kindly providing DNA pol-γ. This work was supported by Cancer Research UK.

PY - 2011/12/15

Y1 - 2011/12/15

N2 - 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-γ. 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.

AB - 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-γ. 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.

KW - DNA oxidation damage

KW - Mitochondrial DNA

KW - Mitochondrial DNA replication

KW - Mitochondrial DNA transcription

KW - Oxidative metabolism

KW - Thiopurine

KW - Ultraviolet A

UR - https://www.scopus.com/pages/publications/82555186987

U2 - 10.1016/j.febslet.2011.10.040

DO - 10.1016/j.febslet.2011.10.040

M3 - Article

C2 - 22062154

AN - SCOPUS:82555186987

SN - 0014-5793

VL - 585

SP - 3941

EP - 3946

JO - FEBS Letters

JF - FEBS Letters

IS - 24

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this