title: Instability of CTG repeats is governed by the position of a DNA base lesion through base excision repair.
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 5'-end of CTG repeats resulted in expansion, whereas a lesion located either in the middle or the 3'-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 β 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.
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA.
authors.forename: Yanhao
authors.initials: Y
authors.lastname: Lai
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.forename: Zunzhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000378:metabolism; D004260:DNA Repair; D005347:Fibroblasts / Q000378:metabolism; D045585:Flap Endonucleases / Q000378:metabolism; D042822:Genomic Instability; D057809:HEK293 Cells; D006801:Humans; D055029:Inverted Repeat Sequences; D051379:Mice; D018384:Oxidative Stress; D017384:Sequence Deletion; D019680:Trinucleotide Repeat Expansion
chemical_list: D019951:DNA Polymerase beta; D045585:Flap Endonucleases