title: A 5', 8-cyclo-2'-deoxypurine lesion induces trinucleotide repeat deletion via a unique lesion bypass by DNA polymerase β.
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.
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, 11200 SW, 8th Street, Miami, FL 33199, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, 11200 SW, 8th Street, Miami, FL 33199, USA.
authors.forename: Yanhao
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, 11200 SW, 8th Street, Miami, FL 33199, USA.
authors.forename: Zhongliang
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: ISOF, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, 40129 Bologna, Italy.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Terzidis
authors.affiliation: ISOF, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, 40129 Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Masi
authors.affiliation: ISOF, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, 40129 Bologna, Italy Institute of Nanoscience and Nanotechnology, N.C.S.R. 'Demokritos', 15341 Agia, Paraskevi, Athens, Greece.
authors.forename: Chryssostomos
authors.initials: C
authors.lastname: Chatgilialoglu
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, 11200 SW, 8th Street, Miami, FL 33199, USA Biomolecular Sciences Institute, School of Integrated Sciences and Humanities, Florida International University, 11200 SW, 8th Street, Miami, FL 33199, USA yualiu@fiu.edu.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D004247:DNA / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000378:metabolism*; D004260:DNA Repair; D004261:DNA Replication; D003839:Deoxyadenosines / Q000737:chemistry*; D045585:Flap Endonucleases / Q000378:metabolism; D017384:Sequence Deletion; D013698:Templates, Genetic; D018911:Trinucleotide Repeats
chemical_list: D003839:Deoxyadenosines; C022262:Okazaki fragments; C056752:8,5'-cyclo-2'-deoxyadenosine; D004247:DNA; D019951:DNA Polymerase beta; D045585:Flap Endonucleases