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.
Highlights
Reactive oxygen species (ROS) generated from environmental stress such as ionizing radiation and endogenous oxidative stress from energy metabolism can result in more than 30 types of oxidized DNA base lesions in the human genome [1,2]
Because cyclo-2 -deoxypurines (cdPus) lesions can readily accumulate in DNA, and an 8-oxoG on the complimentary strand can be efficiently removed for initiating the short-patch or long-patch base excision repair (BER), this allows pol  to encounter and bypass cdPu lesions located at various positions in a Trinucleotide repeats (TNRs) tract during BER
Because previous studies showed that the efficiency of pol  DNA synthesis varied during BER of an oxidized base lesion that was located at different locations in a TNR tract [26,67], we further examined whether the position of a 1-nt gap relative to a template cyclo-2 deoxyadenosine (cdA) in a (CAG)10 tract can modulate the efficiency of pol  lesion bypass synthesis by employing pol  DNA synthesis with the substrates containing a 1-nt gap located upstream or downstream of a template cdA (Figure 3)
Summary
Reactive oxygen species (ROS) generated from environmental stress such as ionizing radiation and endogenous oxidative stress from energy metabolism can result in more than 30 types of oxidized DNA base lesions in the human genome [1,2]. The efficiency of removing a cdPu by NER is 2- to 4-fold less than that of removing other bulky lesions such as a cisB[␣]P-N2-dG adduct [12] This leads to the accumulation of a high level of cdPu lesions in genomic DNA, resulting in blockage of DNA synthesis by human pol ␦/⑀ [13], replication fork stalling and inefficient lesion bypass DNA synthesis by translesion DNA polymerases [14,15,16]. This can subsequently lead to the accumulation of DNA strand breaks that can cause cell death. Because the bypass of a cdPu by translesion DNA polymerases, such as pol and pol , can cause A to T and G to T transversions as well as a G to A transition [14], accumulation of cdPus in the genome may result in mutagenesis and cell death, which are associated with aging, cancer and neurodegeneration [7,17,18,19]
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