A 5', 8-cyclo-2'-deoxypurine lesion induces trinucleotide repeat deletion via a unique lesion bypass by DNA polymerase β.

Authors

Meng Xu, Department of Chemistry and Biochemistry, Florida International UniversityFollow
Yanhao Lai, Department of Chemistry and Biochemistry, Florida International UniversityFollow
Zhongliang Jiang, Department of Chemistry and Biochemistry, Florida International UniversityFollow
Michael A. Terzidis, ISOF, Consiglio Nazionale delle Ricerche
Annalisa Masi, ISOF, Consiglio Nazionale delle Ricerche
Chryssostomos Chatgilialoglu, ISOF, Consiglio Nazionale delle Ricerche; Institute of Nanoscience and Nanotechnology, N.C.S.R.
Yuan Liu, Department of Chemistry and Biochemistry, Florida International University, Miami, FloridaFollow

Date of this Version

11-10-2014

Document Type

Article

Abstract

5′,8-cyclo-2′-deoxypurines (cdPus) are common forms of oxidized DNA lesions resulting from endogenous and environmental oxidative stress such as ionizing radiation. The lesions can only be repaired by nucleotide excision repair with a low efficiency. This results in their accumulation in the genome that leads to stalling of the replication DNA polymerases and poor lesion bypass by translesion DNA polymerases. Trinucleotide repeats (TNRs) consist of tandem repeats of Gs and As and therefore are hotspots of cdPus. In this study, we provided the first evidence that both (5′R)- and (5′S)-5′,8-cyclo-2′-deoxyadenosine (cdA) in a CAG repeat tract caused CTG repeat deletion exclusively during DNA lagging strand maturation and base excision repair. We found that a cdA induced the formation of a CAG loop in the template strand, which was skipped over by DNA polymerase β (pol β) lesion bypass synthesis. This subsequently resulted in the formation of a long flap that was efficiently cleaved by flap endonuclease 1, thereby leading to repeat deletion. Our study indicates that accumulation of cdPus in the human genome can lead to TNR instability via a unique lesion bypass by pol β.

Comments

Published by Oxford University Press on behalf of Nucleic Acids Research.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Recommended Citation

Xu, Meng; Lai, Yanhao; Jiang, Zhongliang; Terzidis, Michael A.; Masi, Annalisa; Chatgilialoglu, Chryssostomos; and Liu, Yuan, "A 5', 8-cyclo-2'-deoxypurine lesion induces trinucleotide repeat deletion via a unique lesion bypass by DNA polymerase β." (2014). Department of Chemistry and Biochemistry. 11.
https://digitalcommons.fiu.edu/chemistry_fac/11