Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane

Cockayne syndrome (CS) is a human premature aging disorder associated with severe developmental deficiencies and neurodegeneration, and phenotypically it resembles some mitochondrial DNA (mtDNA) diseases. Most patients belong to complementation group B, and the CS group B (CSB) protein plays a role...

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Published in:The FASEB journal 2010-07, Vol.24 (7), p.2334-2346
Main Authors: Aamann, Maria D, Sorensen, Martin M, Hvitby, Christina, Berquist, Brian R, Muftuoglu, Meltem, Tian, Jingyan, de Souza-Pinto, Nadja C, Scheibye-Knudsen, Morten, Wilson, David M. III, Stevnsner, Tinna, Bohr, Vilhelm A
Format: Article
Language:English
Subjects:
base excision repair
BER
Cell Line
CSB
DNA Helicases - analysis
DNA Helicases - deficiency
DNA Helicases - physiology
DNA Repair
DNA Repair Enzymes - analysis
DNA Repair Enzymes - deficiency
DNA Repair Enzymes - physiology
DNA, Mitochondrial
Guanine - analogs & derivatives
Guanine - analysis
Humans
Mitochondrial Membranes - chemistry
Mitochondrial Membranes - physiology
Oxidative Stress
Poly-ADP-Ribose Binding Proteins
Research Communications
Uracil - analogs & derivatives
Uracil - analysis
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Summary:Cockayne syndrome (CS) is a human premature aging disorder associated with severe developmental deficiencies and neurodegeneration, and phenotypically it resembles some mitochondrial DNA (mtDNA) diseases. Most patients belong to complementation group B, and the CS group B (CSB) protein plays a role in genomic maintenance and transcriptome regulation. By immunocytochemistry, mitochondrial fractionation, and Western blotting, we demonstrate that CSB localizes to mitochondria in different types of cells, with increased mitochondrial distribution following menadione-induced oxidative stress. Moreover, our results suggest that CSB plays a significant role in mitochondrial base excision repair (BER) regulation. In particular, we find reduced 8-oxo-guanine, uracil, and 5-hydroxy-uracil BER incision activities in CSB-deficient cells compared to wild-type cells. This deficiency correlates with deficient association of the BER activities with the mitochondrial inner membrane, suggesting that CSB may participate in the anchoring of the DNA repair complex. Increased mutation frequency in mtDNA of CSB-deficient cells demonstrates functional significance of the presence of CSB in the mitochondria. The results in total suggest that CSB plays a direct role in mitochondrial BER by helping recruit, stabilize, and/or retain BER proteins in repair complexes associated with the inner mitochondrial membrane, perhaps providing a novel basis for understanding the complex phenotype of this debilitating disorder.--Aamann, M. D., Sorensen, M. M., Hvitby, C., Berquist, B. R., Muftuoglu, M., Tian, J., de Souza-Pinto, N. C., Scheibye-Knudsen, M., Wilson, D. M., III, Stevnsner, T., Bohr, V. A. Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.09-147991