Instability of CTG Repeats is Governed by the Position of a DNA Base Lesion through Base Excision Repair

Authors

Yanhao Lai, Department of Chemistry and Biochemistry, Florida International University, Miami, Florida; Department of Environmental and Occupational Health, West China School of Public Health, Sichuan University, Chengdu, People’s Republic of ChinaFollow
Meng Xu, Department of Chemistry and Biochemistry, Florida International University, Miami, FloridaFollow
Zunzhen Zhang, Department of Environmental and Occupational Health, West China School of Public Health, Sichuan University, Chengdu, People’s Republic of ChinaFollow
Yuan Liu, Department of Chemistry and Biochemistry, Florida International University, Miami, FloridaFollow

Date of this Version

2-26-2013

Document Type

Article

Abstract

Trinucleotide repeat (TNR) expansions and deletions are associated with human neurodegeneration and cancer. However, their underlying mechanisms remain to be elucidated. Recent studies have demonstrated that CAG repeat expansions can be initiated by oxidative DNA base damage and fulfilled by base excision repair (BER), suggesting active roles for oxidative DNA damage and BER in TNR instability. Here, we provide the first evidence that oxidative DNA damage can induce CTG repeat deletions along with limited expansions in human cells. Biochemical characterization of BER in the context of (CTG)20 repeats further revealed that repeat instability correlated with the position of a base lesion in the repeat tract. A lesion located at the 59-end of CTG repeats resulted in expansion, whereas a lesion located either in the middle or the 39-end of the repeats led to deletions only. The positioning effects appeared to be determined by the formation of hairpins at various locations on the template and the damaged strands that were bypassed by DNA polymerase b and processed by flap endonuclease 1 with different efficiency. Our study indicates that the position of a DNA base lesion governs whether TNR is expanded or deleted through BER.

Comments

This article was originally published in PLoS One.

Creative Commons License

This work is licensed under a Creative Commons Attribution 2.0 License.

Recommended Citation

Lai Y, Xu M, Zhang Z, Liu Y (2013) Instability of CTG Repeats Is Governed by the Position of a DNA Base Lesion through Base Excision Repair. PLoS ONE 8(2): e56960. doi:10.1371/journal.pone.0056960