7coc | pdb_00007coc

Ternary complex of DNA polymerase Mu (K438A/Q441A) with 1-nt gapped DNA (T:dGMPNPP)

Structural highlights

7coc is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Ligands:	K, MG, XG4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DPOLM_HUMAN Gap-filling polymerase involved in repair of DNA double-strand breaks by non-homologous end joining (NHEJ). Participates in immunoglobulin (Ig) light chain gene rearrangement in V(D)J recombination.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Pol mu is capable of performing gap-filling repair synthesis in the nonhomologous end joining (NHEJ) pathway. Together with DNA ligase, misincorporation of dGTP opposite the templating T by Pol mu results in a promutagenic T:G mispair, leading to genomic instability. Here, crystal structures and kinetics of Pol mu substituting dGTP for dATP on gapped DNA substrates containing templating T were determined and compared. Pol mu is highly mutagenic on a 2-nt gapped DNA substrate, with T:dGTP base pairing at the 3' end of the gap. Two residues (Lys438 and Gln441) interact with T:dGTP and fine tune the active site microenvironments. The in-crystal misincorporation reaction of Pol mu revealed an unexpected second dGTP in the active site, suggesting its potential mutagenic role among human X family polymerases in NHEJ.

Mechanism of genome instability mediated by human DNA polymerase mu misincorporation.,Guo M, Wang Y, Tang Y, Chen Z, Hou J, Dai J, Wang Y, Wang L, Xu H, Tian B, Hua Y, Zhao Y Nat Commun. 2021 Jun 18;12(1):3759. doi: 10.1038/s41467-021-24096-7. PMID:34145298^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nick McElhinny SA, Ramsden DA. Polymerase mu is a DNA-directed DNA/RNA polymerase. Mol Cell Biol. 2003 Apr;23(7):2309-15. PMID:12640116
↑ Ruiz JF, Juarez R, Garcia-Diaz M, Terrados G, Picher AJ, Gonzalez-Barrera S, Fernandez de Henestrosa AR, Blanco L. Lack of sugar discrimination by human Pol mu requires a single glycine residue. Nucleic Acids Res. 2003 Aug 1;31(15):4441-9. PMID:12888504
↑ Capp JP, Boudsocq F, Besnard AG, Lopez BS, Cazaux C, Hoffmann JS, Canitrot Y. Involvement of DNA polymerase mu in the repair of a specific subset of DNA double-strand breaks in mammalian cells. Nucleic Acids Res. 2007;35(11):3551-60. Epub 2007 May 5. PMID:17483519 doi:https://dx.doi.org/10.1093/nar/gkm243
↑ DeRose EF, Clarkson MW, Gilmore SA, Galban CJ, Tripathy A, Havener JM, Mueller GA, Ramsden DA, London RE, Lee AL. Solution structure of polymerase mu's BRCT Domain reveals an element essential for its role in nonhomologous end joining. Biochemistry. 2007 Oct 30;46(43):12100-10. Epub 2007 Oct 4. PMID:17915942 doi:10.1021/bi7007728
↑ Guo M, Wang Y, Tang Y, Chen Z, Hou J, Dai J, Wang Y, Wang L, Xu H, Tian B, Hua Y, Zhao Y. Mechanism of genome instability mediated by human DNA polymerase mu misincorporation. Nat Commun. 2021 Jun 18;12(1):3759. PMID:34145298 doi:10.1038/s41467-021-24096-7

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OCA

[1] Nick McElhinny SA, Ramsden DA. Polymerase mu is a DNA-directed DNA/RNA polymerase. Mol Cell Biol. 2003 Apr;23(7):2309-15. PMID:12640116

[2] Ruiz JF, Juarez R, Garcia-Diaz M, Terrados G, Picher AJ, Gonzalez-Barrera S, Fernandez de Henestrosa AR, Blanco L. Lack of sugar discrimination by human Pol mu requires a single glycine residue. Nucleic Acids Res. 2003 Aug 1;31(15):4441-9. PMID:12888504

[3] Capp JP, Boudsocq F, Besnard AG, Lopez BS, Cazaux C, Hoffmann JS, Canitrot Y. Involvement of DNA polymerase mu in the repair of a specific subset of DNA double-strand breaks in mammalian cells. Nucleic Acids Res. 2007;35(11):3551-60. Epub 2007 May 5. PMID:17483519 doi:https://dx.doi.org/10.1093/nar/gkm243

[4] DeRose EF, Clarkson MW, Gilmore SA, Galban CJ, Tripathy A, Havener JM, Mueller GA, Ramsden DA, London RE, Lee AL. Solution structure of polymerase mu's BRCT Domain reveals an element essential for its role in nonhomologous end joining. Biochemistry. 2007 Oct 30;46(43):12100-10. Epub 2007 Oct 4. PMID:17915942 doi:10.1021/bi7007728

[5] Guo M, Wang Y, Tang Y, Chen Z, Hou J, Dai J, Wang Y, Wang L, Xu H, Tian B, Hua Y, Zhao Y. Mechanism of genome instability mediated by human DNA polymerase mu misincorporation. Nat Commun. 2021 Jun 18;12(1):3759. PMID:34145298 doi:10.1038/s41467-021-24096-7

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[5]

7coc | pdb_00007coc

Ternary complex of DNA polymerase Mu (K438A/Q441A) with 1-nt gapped DNA (T:dGMPNPP)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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