Mitochondrial translesion DNA synthesis

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ABSTRACT Mitochondrial DNA (mtDNA) integrity is critical for metabolism and cellular energy supply and human health and longevity. Due to lack of repair mechanism and specified translesion synthesis (TLS) polymerase, mtDNA contains higher contents of UV lesions. The high-fidelity mitochondrial DNA polymerase (Pol g) will unavoidably encounter the UV lesions during mtDNA replication. Unlike other high-fidelity DNA polymerases that lack TLS activity, we found Pol g possesses a metal regulated TLS activity. In the presence of magnesium ion, Pol g exhibits no TLS activity, however, in the presence of physiological concentrations of manganese ion alone or Mg/Mn mixture, Pol g can synthesize cross UV lesion cyclobutane dimer with efficiency near that on the non-damaged DNA. We also discovered that Pol g has an extensive lesion recognition network that can sense an upstream lesion as far as 10 base pairs in the presence of Mg2+, but completely ignores the lesion with Mn2+. We hypothesize that Manganese ion can alter the elasticity of Pol g to be able to accommodate bulky lesions for translesion synthesis. we will test the hypothesis by completing the Specific Aims 1) Mechanism of Pol g integrated lesion bypassing, extension, and replication activities, 2) Investigation of Pol g long-range lesion sensing and 3) Biophysical basis for metal-directed Pol g TLS. The proposed studies will illustrate how mitochondrial replicase utilizing the essential metal ions to maintain genome integrity under UV radiation.