Oxidative lesions are removed from DNA primarily via the base excision repair (BER) pathway. BER is carried out through four enzymatic steps, but it is now clear that several other proteins modulate BER efficiency through protein-protein interactions. We and others identified several protein interactions for the core BER enzymes. These protein interactions are physical and functional and together support the """"""""passing of baton"""""""" model, in which BER takes place in different steps supported by individual protein interactions that are components of a repair complex, possibly situated at the DNA lesion. We are studying other protein interactions of OGG1 in order to understand how repair of oxidative lesions is regulated in vivo. We find that OGG1 also interacts with the recombination protein RAD52, suggesting a possible interplay between these two repair pathways. We find a reciprocal functional interaction between these two proteins, in which RAD52 stimulates OGG1 catalytic activity and OGG1 inhibits RAD52-catalysed DNA strand annealing and invasion. Moreover, the physical interaction between OGG1 and RAD52 increases in cells exposed to oxidative stress, indicating that this interaction is important in the cellular response to oxidative DNA damage. More recently we have shown that OGG1 also plays a significant role in the recovery following a stroke. Using the OGG1 knockout (KO) mouse model, we evaluated the importance of OGG1 after permanent middle cerebral artery occlusion, a stroke model. We observed larger cortical infarcts areas and behavior deficits in the OGG1 KO mice than in WT mice. Additionally, in vitro, the cortical neurons isolated from OGG1 KO mice were more vulnerable to oxidative insults. Our results suggest that the ability to repair oxidatively generated DNA damage has implications for the vulnerability of neurons to metabolic and oxidative stress, and additionally on the functional outcomes after stroke. XRCC1 is an essential scaffold protein for single strand break repair. In humans, deficiencies in XRCC1 lead to chromosome instability and increased sensitivity to DNA damaging agents. Recently we evaluated the catalytic activities and protein interaction capabilities of seven different site directed mutants of XRCC1 to investigate their functional significance. We found two that compromised the integrity of the protein, one interfered with XRCC1s interaction with Pol Beta and four had no phenotype. Through such analysis we hope to define how various disease and population based XRCC1 variants might contribute to disease phenotypes associated with XRCC1.
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