The mammalian LIG1 and LIG3 genes encode DNA ligases involved in base excision repair (BER) with the LIG3 gene encoding nuclear and mitochondrial forms of DNA ligase IIIa. The particpation of DNA ligase I (LigI) and DNA ligase IIIa (LigIIIa) in different subpathways of BER is directed by specific protein-protein interactions. In the case of LigI, interactions with proliferating cell nuclear antigen and replication factor C that occur during lagging strand DNA synthesis at the replication fork also appear to mediate the participation of LigI in the long patch subpathway of BER that is associated with DNA replication. Recent results describing how these interactions co-ordinate ligation with the preceding steps in long patch BER will be discussed. In the nucleus, LigIIIa functions in a complex with XRCC1. This protein acts as a scaffold, recruiting other repair factors involved in the short patch subpathway of BER. Gene targeting studies in mouse cells have shown that, while LigIIIa is required for mitochondrial replication and repair, it does not appear to have a major role in nuclear DNA repair. In contrast, we have recently generated a human cell line lacking nuclear LigIIIa that appears to be defective in BER, suggesting that the relative contribution of the long and short patch subpathways of BER may differ between mice and humans. Although BER is critical for the maintenance of the mitochondrial genome, XRCC1 is absent from these organelles and so it is not known how LigIIIa is directed to participate in mitochondrial BER. Recent work on the characterization of protein complexes containing LigIIIa that are likely to be involved in the repair of oxidative DNA damage in mitochondria will be described. Finally, studies with a DNA ligase inhibitor that selectively targets mitochondrial DNA metabolism will be discussed.

Completion of base excision repair by mammalian DNA ligases

248th National Meeting (2014)

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