6‐Thioguanine damages mitochondrial DNA and causes mitochondrial dysfunction in human cells | Zendy

Daehn Ilse | Zendy; Brem Reto | Zendy; Barkauskaite Eva | Zendy; Karran Peter | Zendy

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

Author(s) -

Daehn Ilse,

Brem Reto,

Barkauskaite Eva,

Karran Peter

Publication year - 2011

Publication title -

febs letters

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.593

H-Index - 257

eISSN - 1873-3468

pISSN - 0014-5793

DOI - 10.1016/j.febslet.2011.10.040

Subject(s) - mitochondrial dna , dna , nuclear dna , mitochondrion , chemistry , microbiology and biotechnology , transcription (linguistics) , biology , biochemistry , gene , linguistics , philosophy

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.

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