DNA glycosylases: in DNA repair and beyond

Abstract

The base excision repair machinery protects DNA in cells from the damaging effects of oxidation, alkylation, and deamination; it is specialized to fix single-base damage in the form of small chemical modifications. Base modifications can be mutagenic and/or cytotoxic, depending on how they interfere with the template function of the DNA during replication and transcription. DNA glycosylases play a key role in the elimination of such DNA lesions; they recognize and excise damaged bases, thereby initiating a repair process that restores the regular DNA structure with high accuracy. All glycosylases share a common mode of action for damage recognition; they flip bases out of the DNA helix into a selective active site pocket, the architecture of which permits a sensitive detection of even minor base irregularities. Within the past few years, it has become clear that nature has exploited this ability to read the chemical structure of DNA bases for purposes other than canonical DNA repair. DNA glycosylases have been brought into context with molecular processes relating to innate and adaptive immunity as well as to the control of DNA methylation and epigenetic stability. Here, we summarize the key structural and mechanistic features of DNA glycosylases with a special focus on the mammalian enzymes, and then review the evidence for the newly emerging biological functions beyond the protection of genome integrity.

Emerging links between iron-sulfur clusters and 5-methylcytosine base excision repair in plants

“…In short-patch BER, monofunctional glycosylases require the intervention of an AP endonuclease to generate compatible ends for DNA polymerase β, and then of a DNA ligase to replace a single nucleotide (Jacobs and Schar, 2012). In long-patch BER, bifunctional glycosylases couple base excision with an AP-lyase step, and DNA polymerase δ/ε carry out repair to introduce 2-6 nucleotides, also sealed by a DNA ligase (Jacobs and Schar, 2012). The processes of BER excision and repair synthesis are conserved from bacteria to mammals.…”

Influence of Oxidized Purine Processing on Strand Directionality of Mismatch Repair

“…They differ principally in their substrate specificity and in repair patch size. The specificity of BER is dictated by the enzymes that initiate the process, DNA glycosylases, which recognize and excise a limited number of damaged or modified bases (32). The repair process is thus initiated at the site of the base modification and involves the replacement of one (short patch BER) (33) or only 2-6 (long patch BER) nucleotides (34,35).…”

“…It was performed similarly to the MMR assay except for the following modifications. To track MMR-, MYH-, or OGG1-dependent nucleotide incorporation, the reactions were supplemented with 2 Ci of [␣- 32 32 P]dGMP incorporation in MYH-or OGG1-induced BER was determined from the ratio between the band intensities of fragment a on the autoradiographs and on the GelRed-stained agarose gels.…”

Estudo do papel de mTOR na regulação da atividade de reparo do DNA mitocondrial humano

“…As glicosilases monofuncionais possuem apenas uma atividade de glicosilase, que hidrolisa a ligação N-glicosídica e libera a base alterada. Glicosilases bifuncionais possuem uma atividade adicional, de AP liase, que hidrolisa a ligação fosfodiester no sítio abásico resultante da liberação da base alterada (Jacobs & Schar, 2012). 8-oxoguanina DNA glicosilase (OGG1) e Nei-like DNA glicosilase 3 (NEIL3) podem funcionar tanto como glicosilases monofuncionais como bifuncionais (Svilar et al, 2011).…”