Alleviation of C⋅C Mismatches in DNA by the Fpg Protein

Overview

Journal Front Microbiol

Specialty Microbiology

Date 2021 Jul 19

PMID 34276575

Authors

Almaz Nigatu Tesfahun

Marina Alexeeva

Migle Tomkuviene

Aysha Arshad

Prashanna Guragain

Arne Klungland

Saulius Klimasauskas

Peter Ruoff

Svein Bjelland

Affiliations

Soon will be listed here.

Abstract

DNA polymerase III mis-insertion may, where not corrected by its 3'→ 5' exonuclease or the mismatch repair (MMR) function, result in all possible non-cognate base pairs in DNA generating base substitutions. The most thermodynamically unstable base pair, the cytosine (C)⋅C mismatch, destabilizes adjacent base pairs, is resistant to correction by MMR in , and its repair mechanism remains elusive. We present here evidence that C⋅C mismatch can be processed by base excision repair initiated by the formamidopyrimidine-DNA glycosylase (Fpg) protein. The for C⋅C is, however, 2.5 to 10 times lower than for its primary substrate 8-oxoguanine (oxoG)⋅C, but approaches those for 5,6-dihydrothymine (dHT)⋅C and thymine glycol (Tg)⋅C. The values are all in the same range, which indicates efficient recognition of C⋅C mismatches in DNA. Fpg activity was also exhibited for the thymine (T)⋅T mismatch and for - and/or 5-methylated C opposite C or T, Fpg activity being enabled on a broad spectrum of DNA lesions and mismatches by the flexibility of the active site loop. We hypothesize that Fpg plays a role in resolving C⋅C in particular, but also other pyrimidine⋅pyrimidine mismatches, which increases survival at the cost of some mutagenesis.

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