Global deformation facilitates flipping of damaged 8-oxo-guanine and guanine in DNA

Giuseppe La Rosa, Martin Zacharias

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Oxidation of guanine (Gua) to form 7,8-dihydro-8- oxoguanine (8oxoG) is a frequent mutagenic DNA lesion. DNA repair glycosylases such as the bacterial MutM can effciently recognize and eliminate the 8oxoG damage by base excision. The base excision requires a 8oxoG looping out (flipping) from an intrahelical base paired to an extrahelical state where the damaged base is in the enzyme active site. It is still unclear how the damage is identified and flipped from an energetically stable stacked and paired state without any external energy source. Free energy simulations have been employed to study the flipping process for globally deformed DNA conformational states. DNA deformations were generated by systematically untwisting the DNA to mimic its conformation in repair enzyme encounter complex. The simulations indicate that global DNA untwisting deformation toward the enzyme bound form alone (without protein) significantly reduces the penalty for damage flipping to about half of the penalty observed in regular DNA. The finding offers a mechanistic explanation how binding free energy that is transformed to binding induced DNA deformation facilitates flipping and helps to rapidly detect a damaged base. It is likely of general relevance since repair enzyme binding frequently results in significant deformation of the target DNA.

Original languageEnglish
Pages (from-to)9591-9599
Number of pages9
JournalNucleic Acids Research
Volume44
Issue number20
DOIs
StatePublished - 2016
Externally publishedYes

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