The intricate structural chemistry of base excision repair machinery: implications for DNA damage recognition, removal, and repair.

Abstract:

Three-dimensional structures of DNA N-glycosylases and N-glycosylase/apyrimidine/apurine (AP)-lyase enzymes and other critical components of base excision repair (BER) machinery including structure-specific nuclease, repair polymerase, DNA ligase, and PCNA tethering complexes reveal the overall unity of the simple cut and patch process of DNA repair for damaged bases. In general, the damage-specific excision is initiated by structurally-variable DNA glycosylases targeted to distinct base lesions. This committed excision step is followed by a subsequent damage-general processing of the resulting abasic sites and 3' termini, the insertion of the correct base by a repair DNA polymerase, and finally sealing the nicked backbone by DNA ligase. However, recent structures of protein-DNA and protein-protein complexes and other BER machinery are providing a more in-depth look into the intricate functional diversity and complexity of maintaining genomic integrity despite very high levels of constant DNA base damage from endogenous as well as environmental agents. Here we focus on key discoveries concerning BER structural biology that speak to better understanding the damage recognition, reaction mechanisms, conformational controls, coordinated handoffs, and biological activities including links to cancer. As the three-dimensional crystal and NMR structures for the protein and DNA complexes of all major components of the BER system have now been determined, we provide here a relatively complete description of the key complexes starting from DNA base damage detection and excision to the final ligation process. As our understanding of BER structural biology and the molecular basis for cancer improve, we predict that there will be multiple links joining BER enzyme mutations and cancer predispositions, such as now seen for MYH. Currently, structural results are realizing the promise that high-resolution structures provide detailed insights into how these BER proteins function to specifically recognize, remove, and repair DNA base damage without the release of toxic and mutagenic intermediates.

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