User:Wally Novak/Sandbox Miller

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Revision as of 18:27, 10 October 2016

DNA ligases are a group of proteins responsible for the joining DNA fragments which arise from various cellular events: ligating Okazaki fragments from replication, various repair mechanisms, and recombination. ^[1] The ligation proceeds via a three step process uniting the 3'-OH to the 5'-phosphate with an ATP or NAD+ cofactor. ^[2] DNA ligase I is a member of this family expressed throughout eukaryotes. Included is a summary of its functionality covering the conserved structural domains, ligating mechanism, and involvement in replication as well as DNA repair mechanisms.

Structural Domains

DNA ligase I has four structural domains spread over a 919 residue monomeric protein. Three of the four domains are highlighted in the . The DNA-binding domain (DBD) is in red; the adenylation domain (AdD), green; the OB-fold domain (OBD), yellow; and the DNA, grey. The first 232 residues containing domains that interact with other regulative proteins were excluded from the source structure that Ellenberger and colleagues studied.^[3]

The DBD has straightforward function, the binding of DNA, which it accomplishes using mostly polar residues with some basic, cationic ones along the minor groove of the DNA.^[4] Remarkably, the stabilization of the strand opposite the nick in a partially unwound state by the DBD facilitates ligation in trans.^[5] The AdD serves as the catalytic core of DNA ligase I and operates via a highly conserved Lys residue.^[6] The OBD actually has multiple conformations depending on whether or not DNA is bound.^[7] Upon DNA binding, the OBD - Phe 635 and 872 sit in the minor groove and perhaps π-stack while Asp 570 and Arg 871 form salt-bridges connecting the AdD and OBD.^[8] Unsurprisingly, most of these DNA binding interactions appear to be facilitated by metals.

The remaining N-terminus domain of DNA ligase I is involved in regulating interactions with outside proteins. Proliferating cell nuclear antigen (PCNA), DNA polymerase β (POLB), and replication factor C (RFC) are known to bind in to this domain of DNA ligase I.^[9] PCNA, in fact, appears to lock DNA ligase into its catalytic state thereby increasing throughput.^[10] The N-terminus interactive domain also has three Ser which can be phosphorylated; the phosphorylation of these residues at various parts of the cell cycle suggest regulation by post-translational modification.^[11]

Ligating Mechanism

Okazaki Fragments and Replication

DNA Repair

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References

1. ↑ Ellenberger, T.; Tomkinson, A.E. Annu. Rev. Biochem. 2008, 77, 13-38; Shuman, S. J. Biol. Chem. 2009, 284, 17365-17369.
2. ↑ Ellenberger, T.; Tomkinson, A.E. Annu. Rev. Biochem. 2008, 77, 13-38; Shuman, S. J. Biol. Chem. 2009, 284, 17365-17369; Tomkinson, A.E.; Vijayakumar, S.; Pascal, J.M.; Ellenberger, T. Chem. Rev. 2006, 106, 687-669.
3. ↑ Pascal, J.M.; O'Brien, P.J.; Tomkinson, A.E.; Ellenberger, T. Nature 2004, 432, 473-478.
4. ↑ Pascal, J.M.; O'Brien, P.J.; Tomkinson, A.E.; Ellenberger, T. Nature 2004, 432, 473-478.
5. ↑ Tomkinson, A.E.; Vijayakumar, S.; Pascal, J.M.; Ellenberger, T. Chem. Rev. 2006, 106, 687-669.
6. ↑ Ellenberger, T.; Tomkinson, A.E. Annu. Rev. Biochem. 2008, 77, 13-38.
7. ↑ Pascal, J.M.; O'Brien, P.J.; Tomkinson, A.E.; Ellenberger, T. Nature 2004, 432, 473-478.
8. ↑ Ellenberger, T.; Tomkinson, A.E. Annu. Rev. Biochem. 2008, 77, 13-38; Pascal, J.M.; O'Brien, P.J.; Tomkinson, A.E.; Ellenberger, T. Nature 2004, 432, 473-478.
9. ↑ Tomkinson, A.E.; Vijayakumar, S.; Pascal, J.M.; Ellenberger, T. Chem. Rev. 2006, 106, 687-669;Pascal, J.M.; O'Brien, P.J.; Tomkinson, A.E.; Ellenberger, T. Nature 2004, 432, 473-478.
10. ↑ Pascal, J.M.; Tsodikov, O.V.; Hura, G.L.; Song, W.; Cotner, E.A.; Classen, S.; Tomkinson, A.E.; Tainer, J.A.; Ellenberger, T. Mol. Cell 2006, 24, 279-291
11. ↑ Ellenberger, T.; Tomkinson, A.E. Annu. Rev. Biochem. 2008, 77, 13-38.

^[1] to the rescue.