Polymerase and Proofreading Exonuclease Domains in the DNA Polymerase γ and Nuclear-encoded RNA Polymerase of the Human Mitochondria and Identification of Mitochondrial Disease Mutations in the Polymerase Active Site Region of DNA Polymerase γ
Department of Molecular Microbiology, School of Biotechnology, Madurai Kamaraj University, Madurai – 625 021, India.
Research Article
World Journal of Advanced Research and Reviews, 2024, 21(02), 979–1005
Article DOI: 10.30574/wjarr.2024.21.2.0512
Publication history:
Received on 03 January 2024; revised on 11 February 2024; accepted on 13 February 2024
Abstract:
Recent reports have made it clear that mutations in the mitochondrial DNA (mtDNA) polymerase γ (POLG1) are a major cause of many human diseases. Mutations in the mtDNA polymerase leads to defective oxidative phosphorylation and ATP production, resulting in many mitochondrial diseases. For their mitochondrial genome replication, humans and animals use POLG1, whose catalytic site is essentially similar to the E. coli DNA polymerase I (DNA pol I). Multiple sequence alignment (MSA) analysis have shown that the POLG1 and E. coli DNA pol I use identical amino acids in their polymerase catalytic sites, viz. –943R-4EHAKI1FNYGRI955Y8G- (human DNA pol γ) as –R-4RSAKA1INFGLIY8G- (E. coli DNA pol I). However, the human POLG1 shows only 31.25% identity with the E. coli DNA pol I, suggesting a highly divergent evolution. Mutation(s) in the POLG1 gene is one of the most common causes of many inherited mitochondrial diseases in children and adults. Depending on their location within the enzyme, mutations either lead to mtDNA depletion or accumulation of multiple mtDNA deletions leading to various mitochondrial diseases. The most common POLG1 dominant mutation, viz. Y955→H/C, which lead to a severe, early-onset of multi-systemic mitochondrial disease with bilateral sensorineural hearing loss, cataract, myopathy, and liver failure is located in the template-binding pair of the polymerase catalytic site region by MSA. Another dominant mutation, R943→H/C is observed in patients with Progressive External Ophthalmoplegia (adPEO, an autosomal, dominant, heritable mitochondrial disorder) is located in the nucleoside triphosphate (NTP) selection amino acid in the polymerase catalytic site region. The nuclear-encoded RNA polymerase (NEP) is imported from the nucleus and involves in the transcription of all the mitochondrial genes. The human mitochondrial NEP showed 39.30%, 40.12% and 26.98% identities to the NEPs of the mitochondria and chloroplasts of Arabidopsis thaliana, and T7 RNA polymerase, respectively, suggesting that the human and plant mitochondrial NEPs are distinctly different. Interestingly, the human NEP’s catalytic core is almost completely conserved in the plant mitochondrial and chloroplast NEPs, viz. –R-4KVVKQ1TVMTVVY8G- (Human) and –R-4KLVKQ1TVMTSVY8G- (A. Thaliana). Furthermore, the mitochondrial NEP’s catalytic core from human and different animal sources is remarkably conserved and is in close agreement with other NEPs of plant sources. Both the human DNA pol γ and NEP possess a typical template-binding pair (-YG-), a basic catalytic amino acid (K) to initiate catalysis and a basic nucleotide selection amino acid R at -4 from the catalytic K. The PR exonucleases of POLG1 and NEP belong to the DEDD-superfamily of exonucleases and uses a Y or H as the proton acceptor, respectively.
Keywords:
Human mitochondria; Human mitochondrial diseases; DNA Polymerase γ; Nuclear-encoded RNA polymerase; Polymerase active sites; Proofreading exonucleases; Proofreading exonuclease active sites
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