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FUNCTION Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA). Replicates both heavy and light strands of the circular mtDNA genome using a single-stranded DNA template, RNA primers and the four deoxyribonucleoside triphosphates as substrates (PubMed:11477093, PubMed:11897778, PubMed:15917273, PubMed:19837034, PubMed:9558343). Has 5' -> 3' polymerase activity. Functionally interacts with TWNK and SSBP1 at the replication fork to form a highly processive replisome, where TWNK unwinds the double-stranded DNA template prior to replication and SSBP1 covers the parental heavy strand to enable continuous replication of the entire mitochondrial genome. A single nucleotide incorporation cycle includes binding of the incoming nucleotide at the insertion site, a phosphodiester bond formation reaction that extends the 3'-end of the primer DNA, and translocation of the primer terminus to the post-insertion site. After completing replication of a mtDNA strand, mediates 3' -> 5' exonucleolytic degradation at the nick to enable proper ligation (PubMed:11477093, PubMed:11897778, PubMed:15167897, PubMed:15917273, PubMed:19837034, PubMed:26095671, PubMed:9558343). Highly accurate due to high nucleotide selectivity and 3' -> 5' exonucleolytic proofreading. Proficiently corrects base substitutions, single-base additions and deletions in non-repetitive sequences and short repeats, but displays lower proofreading activity when replicating longer homopolymeric stretches. Exerts exonuclease activity toward single-stranded DNA and double-stranded DNA containing 3'-terminal mispairs. When a misincorporation occurs, transitions from replication to a pro-nucleolytic editing mode and removes the missincorporated nucleoside in the exonuclease active site. Proceeds via an SN2 nucleolytic mechanism in which Asp-198 catalyzes phosphodiester bond hydrolysis and Glu-200 stabilizes the leaving group. As a result the primer strand becomes one nucleotide shorter and is positioned in the post-insertion site, ready to resume DNA synthesis (PubMed:10827171, PubMed:11477094, PubMed:11504725, PubMed:37202477). Exerts 5'-deoxyribose phosphate (dRP) lyase activity and mediates repair-associated mtDNA synthesis (gap filling) in base-excision repair pathway. Catalyzes the release of the 5'-terminal 2-deoxyribose-5-phosphate sugar moiety from incised apurinic/apyrimidinic (AP) sites to produce a substrate for DNA ligase. The dRP lyase reaction does not require divalent metal ions and likely proceeds via a Schiff base intermediate in a beta-elimination reaction mechanism (PubMed:9770471).CATALYTIC ACTIVITY DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphateCATALYTIC ACTIVITY a 3'-end 2'-deoxyribonucleotidyl-deoxyribonucleotide-DNA + H2O = a 3'-end 2'-deoxyribonucleotide-DNA + a 2'-deoxyribonucleoside 5'-phosphate + H(+)CATALYTIC ACTIVITY a 5'-end 2'-deoxyribose-2'-deoxyribonucleotide-DNA = (2E,4S)-4-hydroxypenten-2-al-5-phosphate + a 5'-end 5'-phospho-2'-deoxyribonucleoside-DNA + H(+)COFACTOR Inhibited by dideoxynucleotides such as antiviral agent zalcitabine.BIOPHYSICOCHEMICAL PROPERTIES Heterotrimer composed of a catalytic subunit and a homodimer of accessory subunits (POLG:POLG2) (PubMed:11477093, PubMed:11477094, PubMed:15167897, PubMed:19837034, PubMed:26056153, PubMed:37202477). Interacts with TTC3 (PubMed:29290964). Interacts with LIG3 (PubMed:33855352).INTERACTION The polymerase domain encompasses three conserved active site motifs: Pol A (residues 887-896), Pol B (residues 943-958) and Pol C (residues 1134-1141). Binds the incoming dNTPs and undergoes an open to close coformation change to catalyze the formation of phosphodiester bond.DOMAIN The 3' -> 5' exonuclease domain comprises three conserved active site motifs: Exo I (residues 196-200), Exo II (residues 267-275) and Exo III (residues 395-403). Proofreads the newly synthesized DNA strand.DOMAIN The trigger loop contracts to enable correctly matched primer-template pair entry into the polymerase domain and extends to preclude the mismatched one.DOMAIN The accessory determinant domain (AID) interacts with POLG2 proximal monomer.POLYMORPHISM The poly-Gln region seems to be polymorphic.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.SIMILARITY Belongs to the DNA polymerase type-A family.
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