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The Impact of SNP-Induced Amino Acid Substitutions L19P and G66R in the dRP-Lyase Domain of Human DNA Polymerase β on Enzyme Activities.
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- المؤلفون: Kladova, Olga A.1 (AUTHOR) ; Tyugashev, Timofey E.1 (AUTHOR); Yakimov, Denis V.2 (AUTHOR); Mikushina, Elena S.1 (AUTHOR); Novopashina, Daria S.1 (AUTHOR); Kuznetsov, Nikita A.1,2 (AUTHOR); Kuznetsova, Aleksandra A.1 (AUTHOR)
- المصدر:
International Journal of Molecular Sciences. Apr2024, Vol. 25 Issue 8, p4182. 19p.
- الموضوع:
- معلومة اضافية
- نبذة مختصرة :
Base excision repair (BER), which involves the sequential activity of DNA glycosylases, apurinic/apyrimidinic endonucleases, DNA polymerases, and DNA ligases, is one of the enzymatic systems that preserve the integrity of the genome. Normal BER is effective, but due to single-nucleotide polymorphisms (SNPs), the enzymes themselves—whose main function is to identify and eliminate damaged bases—can undergo amino acid changes. One of the enzymes in BER is DNA polymerase β (Polβ), whose function is to fill gaps in DNA. SNPs can significantly affect the catalytic activity of an enzyme by causing an amino acid substitution. In this work, pre-steady-state kinetic analyses and molecular dynamics simulations were used to examine the activity of naturally occurring variants of Polβ that have the substitutions L19P and G66R in the dRP-lyase domain. Despite the substantial distance between the dRP-lyase domain and the nucleotidyltransferase active site, it was found that the capacity to form a complex with DNA and with an incoming dNTP is significantly altered by these substitutions. Therefore, the lower activity of the tested polymorphic variants may be associated with a greater number of unrepaired DNA lesions. [ABSTRACT FROM AUTHOR]
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