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Review
. 2010 Oct;20(5):320-8.
doi: 10.1016/j.semcancer.2010.10.010. Epub 2010 Oct 16.

Variant base excision repair proteins: contributors to genomic instability

Antonia A Nemec  1 , Susan S Wallace, Joann B Sweasy
Affiliations
Review

Variant base excision repair proteins: contributors to genomic instability

Antonia A Nemec et al. Semin Cancer Biol. 2010 Oct.

Abstract

Cells sustain endogenous DNA damage at rates greater than 20,000 DNA lesions per cell per day. These damages occur largely as a result of the inherently unstable nature of DNA and the presence of reactive oxygen species within cells. The base excision repair system removes the majority of DNA lesions resulting from endogenous DNA damage. There are several enzymes that function during base excision repair. Importantly, there are over 100 germline single nucleotide polymorphisms in genes that function in base excision repair and that result in non-synonymous amino acid substitutions in the proteins they encode. Somatic variants of these enzymes are also found in human tumors. Variant repair enzymes catalyze aberrant base excision repair. Aberrant base excision repair combined with continuous endogenous DNA damage over time has the potential to lead to a mutator phenotype. Mutations that arise in key growth control genes, imbalances in chromosome number, chromosomal translocations, and loss of heterozygosity can result in the initiation of human cancer or its progression.

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Figures

Figure 1
Figure 1. The BER pathway
There are five major steps in the BER pathway: 1) excision of the damaged base; 2) AP site incision; 3) modification of the ends of the DNA break; 4) gap filling; and 5) ligation of the nick. For a monofunctional glycosylase (i.e. MBD4), the glycosylase removes the damaged base leaving an abasic site. Ape1 incises the abasic site leaving a 3′ OH and 5′ dRP. Polβ removes the dRP group with its lyase activity and fills in the missing nucleotide. In the case of bifunctional glycosylases (i.e. OGG1), the damaged base is removed and the glycosylase incises the abasic site leaving a 3′ 4-OH pentenal phosphate (4-OH-PP) and 5′ phosphate. Ape1 modifies the end to 3′ OH and Polβ fills in the gap. In an Ape1-independent pathway, bifunctional glycosylases (i.e. Neils 1 and 2) remove the damaged base and incise the abasic site via with β,δ elimination, leaving 3′ and 5′ phosphates. PNKP modifies the 3′ end to an OH and Pol β fills in the gap. In the final step, the DNA is ligated by the XRCC1/LIGIIIα complex.
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