Structure-specific roles for PolG2-DNA complexes in maintenance and replication of mitochondrial DNA.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

DNA Polymerase gamma*/genetics ; DNA Polymerase gamma*/metabolism ; DNA, Mitochondrial*/genetics ; DNA, Mitochondrial*/metabolism; Humans ; DNA Replication/genetics ; DNA-Directed DNA Polymerase/metabolism ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondrial Diseases/genetics ; Mitochondrial Diseases/metabolism

The homodimeric PolG2 accessory subunit of the mitochondrial DNA polymerase gamma (Pol γ) enhances DNA binding and processive DNA synthesis by the PolG catalytic subunit. PolG2 also directly binds DNA, although the underlying molecular basis and functional significance are unknown. Here, data from Atomic Force Microscopy (AFM) and X-ray structures of PolG2-DNA complexes define dimeric and hexameric PolG2 DNA binding modes. Targeted disruption of PolG2 DNA-binding interfaces impairs processive DNA synthesis without diminishing Pol γ subunit affinities. In addition, a structure-specific DNA-binding role for PolG2 oligomers is supported by X-ray structures and AFM showing that oligomeric PolG2 localizes to DNA crossings and targets forked DNA structures resembling the mitochondrial D-loop. Overall, data indicate that PolG2 DNA binding has both PolG-dependent and -independent functions in mitochondrial DNA replication and maintenance, which provide new insight into molecular defects associated with PolG2 disruption in mitochondrial disease.
(Published by Oxford University Press on behalf of Nucleic Acids Research 2023.)

Science. 2016 Jul 15;353(6296):aaf5549. (PMID: 27418514)
Nature. 1981 Apr 9;290(5806):457-65. (PMID: 7219534)
J Biol Chem. 2017 Mar 10;292(10):4198-4209. (PMID: 28154168)
Nat Genet. 2013 Feb;45(2):214-9. (PMID: 23313956)
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32. (PMID: 15572765)
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. (PMID: 20124702)
Nucleic Acids Res. 2009 Sep;37(17):5701-13. (PMID: 19625489)
Nat Commun. 2018 Jun 27;9(1):2491. (PMID: 29950568)
Nucleic Acids Res. 2000 Mar 1;28(5):1237-44. (PMID: 10666468)
J Biol Chem. 2010 Jan 8;285(2):1490-9. (PMID: 19858216)
EMBO J. 2015 Jul 14;34(14):1959-70. (PMID: 26056153)
Am J Hum Genet. 2006 Jun;78(6):1026-34. (PMID: 16685652)
J Biol Chem. 2020 Dec 18;295(51):17802-17815. (PMID: 33454015)
Nat Commun. 2018 Mar 23;9(1):1202. (PMID: 29572490)
Hum Mol Genet. 2013 Mar 1;22(5):1017-25. (PMID: 23197651)
J Biol Chem. 2002 Dec 20;277(51):50008-14. (PMID: 12379656)
Nat Rev Mol Cell Biol. 2018 Feb;19(2):77-92. (PMID: 28792006)
Curr Opin Genet Dev. 2016 Jun;38:52-62. (PMID: 27065468)
Mol Cell. 2001 Jan;7(1):43-54. (PMID: 11172710)
Nature. 2020 May;581(7809):434-443. (PMID: 32461654)
Science. 2004 Dec 17;306(5704):2098-101. (PMID: 15604407)
Cell. 2009 Oct 16;139(2):312-24. (PMID: 19837034)
Hum Mol Genet. 2011 Aug 1;20(15):3052-66. (PMID: 21555342)
Exp Gerontol. 2014 Aug;56:175-81. (PMID: 24709344)
Methods Enzymol. 1997;276:307-26. (PMID: 27754618)
Bio Protoc. 2021 Sep 05;11(17):e4139. (PMID: 34604445)
Sci Rep. 2016 Feb 09;6:20513. (PMID: 26856421)
Chem Rev. 2006 Feb;106(2):383-405. (PMID: 16464011)
J Biol Chem. 2005 Dec 30;280(52):42568-72. (PMID: 16204246)
J Mol Biol. 2006 May 19;358(5):1229-43. (PMID: 16574152)
Nucleic Acids Res. 2021 May 21;49(9):5230-5248. (PMID: 33956154)
Biochemistry. 1998 Jul 21;37(29):10529-39. (PMID: 9671525)
Methods. 2010 Aug;51(4):379-84. (PMID: 20176107)
EMBO J. 2004 Jun 16;23(12):2423-9. (PMID: 15167897)
Proc Natl Acad Sci U S A. 1971 Sep;68(9):2252-7. (PMID: 5289384)
Biochemistry. 2000 Feb 22;39(7):1702-8. (PMID: 10677218)
J Biol Chem. 2020 Apr 24;295(17):5564-5576. (PMID: 32213598)
Hum Mol Genet. 2015 Sep 15;24(18):5184-97. (PMID: 26123486)
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9527-32. (PMID: 10449726)
Mitochondrion. 2012 Mar;12(2):313-9. (PMID: 22155748)
J Biol Chem. 1999 Dec 31;274(53):38197-203. (PMID: 10608893)
Nucleic Acids Res. 2016 Jul 8;44(12):5861-71. (PMID: 27220468)
PLoS One. 2018 Aug 29;13(8):e0203198. (PMID: 30157269)
Proc Natl Acad Sci U S A. 1981 Oct;78(10):6116-20. (PMID: 6273850)
Proc Natl Acad Sci U S A. 1990 Mar;87(5):1744-8. (PMID: 2155424)
J Biol Chem. 2018 Jan 19;293(3):1054-1069. (PMID: 29175904)
Nucleic Acids Res. 2018 Jan 4;46(D1):D1062-D1067. (PMID: 29165669)

P30 ES025128 United States ES NIEHS NIH HHS; R01 GM123246 United States GM NIGMS NIH HHS; Z01ES065078 United States NH NIH HHS

EC 2.7.7.7 (DNA Polymerase gamma)
0 (DNA, Mitochondrial)
EC 2.7.7.7 (DNA-Directed DNA Polymerase)
EC 2.7.7.7 (POLG2 protein, human)

Date Created: 20230818 Date Completed: 20240205 Latest Revision: 20240210

20240210

PMC10570022

10.1093/nar/gkad679

37592734