Research output: Contribution to journal › Article › peer-review
Thymines opposite to bulky aristolactam-DNA adducts in duplex DNA are not targeted by human thymine-DNA glycosylase. / Manapkyzy, Diana; Zhamanbayeva, Gulzhan; Sidorenko, Viktoriya et al.
In: PeerJ, Vol. 13, 04.07.2025, p. e19577.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Thymines opposite to bulky aristolactam-DNA adducts in duplex DNA are not targeted by human thymine-DNA glycosylase
AU - Manapkyzy, Diana
AU - Zhamanbayeva, Gulzhan
AU - Sidorenko, Viktoriya
AU - Bonala, Radha
AU - Johnson, Francis
AU - Matkarimov, Bakhyt T.
AU - Zharkov, Dmitry
AU - Saparbaev, Murat K.
AU - Taipakova, Sabira
N1 - Thymines opposite to bulky aristolactam-DNA adducts in duplex DNA are not targeted by human thymine-DNA glycosylase / D. Manapkyzy, G. Zhamanbayeva, V. Sidorenko, R. Bonala, F. Johnson, B. T. Matkarimov, D. Zharkov, M. K. Saparbaev, S. Taipakovav // PeerJ. – 2025. – Vol. 13. – P. e19577. – DOI 10.7717/peerj.19577
PY - 2025/7/4
Y1 - 2025/7/4
N2 - BackgroundConsumption of aristolochic acids (AA) from the plant Aristolochia results in the formation of bulky aristolactam-dA (dA-AL) and aristolactam-dG (dG-AL) adducts in cellular DNA ultimately leading to the development of urothelial cancer. Intriguingly, the dA-AL adducts induce A•T→T•A transversions in tumor cells preferentially in CpA*→TpG context. The human mismatch-specific thymine-DNA glycosylase (TDG) protects cells against mutagenesis induced by spontaneous deamination of 5-methylcytosine (5mC) by removing thymine opposite to guanine in a CpG context in the base excision repair (BER) pathway. Nevertheless, challenges for DNA glycosylases to the faithful discrimination between non-damaged and damaged DNA strands do exist, such as mismatched pairs between two canonical bases, which may result due to DNA polymerase errors during replication. Previously, we demonstrated that TDG is prone to aberrant excision of T opposite to damaged adenine in duplex DNA in CpA*/TpG context.MethodsIn the present work, using in vitro reconstitution assays, we investigated whether TDG participates in the aberrant removal of thymine opposite to dA-AL adducts in duplex DNA.ResultsWe have demonstrated that TDG either does not excise thymine or does so with extremely low efficiency when it is paired with dA-AL or dG-ALII adducts in duplex DNA. At the same time, TDG excises with high efficiency thymine opposite to guanine and hypoxanthine in T•G and T•Hx mispairs.DiscussionThese findings strongly suggest that the human TDG is not involved in the aberrant DNA repair of AA-induced DNA damage.
AB - BackgroundConsumption of aristolochic acids (AA) from the plant Aristolochia results in the formation of bulky aristolactam-dA (dA-AL) and aristolactam-dG (dG-AL) adducts in cellular DNA ultimately leading to the development of urothelial cancer. Intriguingly, the dA-AL adducts induce A•T→T•A transversions in tumor cells preferentially in CpA*→TpG context. The human mismatch-specific thymine-DNA glycosylase (TDG) protects cells against mutagenesis induced by spontaneous deamination of 5-methylcytosine (5mC) by removing thymine opposite to guanine in a CpG context in the base excision repair (BER) pathway. Nevertheless, challenges for DNA glycosylases to the faithful discrimination between non-damaged and damaged DNA strands do exist, such as mismatched pairs between two canonical bases, which may result due to DNA polymerase errors during replication. Previously, we demonstrated that TDG is prone to aberrant excision of T opposite to damaged adenine in duplex DNA in CpA*/TpG context.MethodsIn the present work, using in vitro reconstitution assays, we investigated whether TDG participates in the aberrant removal of thymine opposite to dA-AL adducts in duplex DNA.ResultsWe have demonstrated that TDG either does not excise thymine or does so with extremely low efficiency when it is paired with dA-AL or dG-ALII adducts in duplex DNA. At the same time, TDG excises with high efficiency thymine opposite to guanine and hypoxanthine in T•G and T•Hx mispairs.DiscussionThese findings strongly suggest that the human TDG is not involved in the aberrant DNA repair of AA-induced DNA damage.
KW - DNA glycosylase
KW - DNA repair
KW - Base excision repair
KW - Aristolochic acid
KW - Aristolactam-adenine adduct
KW - T to A transversions
KW - Mutational signature
KW - Thymine-DNA glycosylase
KW - Aberrant DNA repair
KW - Aristolactam-guanine adduct
UR - https://www.mendeley.com/catalogue/5d1cff6a-b96e-3d62-90c8-b7b152c05791/
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=105018617359&origin=inward
U2 - 10.7717/peerj.19577
DO - 10.7717/peerj.19577
M3 - Article
C2 - 40625924
VL - 13
SP - e19577
JO - PeerJ
JF - PeerJ
SN - 2167-8359
ER -
ID: 70964287