Journal Article

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

Meng Xu, Yanhao Lai, Zhongliang Jiang, Michael A. Terzidis, Annalisa Masi, Chryssostomos Chatgilialoglu and Yuan Liu

in Nucleic Acids Research

Volume 42, issue 22, pages 13749-13763
Published in print December 2014 | ISSN: 0305-1048
Published online November 2014 | e-ISSN: 1362-4962 | DOI: http://dx.doi.org/10.1093/nar/gku1239

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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.

Journal Article.  9132 words.  Illustrated.

Subjects: Chemistry ; Biochemistry ; Bioinformatics and Computational Biology ; Genetics and Genomics ; Molecular and Cell Biology

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