DNA ligase

From Proteopedia

1 Function
2 Disease
3 Structural highlights
4 3D Structures of DNA ligase

Function

DNA ligase (LigD) is an enzyme which repairs single-stranded breaks in a double-stranded DNA. LigD is activated, in a species-dependent manner, by hydrolysis of ATP or NAD+. See also ATP-dependent DNA ligase from bacteriophage T7.

Mammalian LigD I ligates the nascent DNA of the lagging strand.
LigD III complexes with XRCC1 in the process of nucleotide excision repair.
LigD IV complexes with XRCC4 and catalyzes the last step in the non-homologous DNA end joining.

See more details in ATP-Dependent DNA Ligase (Bacteriophage T7).

Disease

Known disease associated with this structure: DNA ligase I deficiency OMIM:[126391] The expression of DNA ligase I has been directly linked to cancer in humans. The enzyme is found most in proliferating cells and much less often in nondividing cells. In particular, in malignant tumors, the DNA ligase I enzyme was expressed much more compared to the DNA ligase I enzyme in normal tissues and their peripheral lymphocytes. Further experimentation showed that tumor cell growth rate was successfully decreased when antisense oligonucleotides targeting the mRNA of DNA ligase I were present. This suggests that DNA ligase I could be a good target for new anticancer studies.

A specific point mutation (46BR in the mouse Lig1 gene) in DNA ligase I has also been linked as a cause for genome instability and cancer in humans. One possible reason for this is the accumulation of DNA fragments that are no longer ligated by the mutant DNA ligase I enzyme.

Structural highlights

Human LigD IV contains several domains: DNA-binding domain (residues 1-240); adenylation domain (residues 268-405) and the ca. 100 amino acid long BRCT motifs (residues 654-911). In the ATP-dependent LigD the ATP binds between 2 symmetry related LigD molecules.

in ATP-dependent DNA ligase from S. solfataricus (2hix). ^[1]

3D Structures of DNA ligase

DNA ligase 3D structures

References

↑ Pascal JM, Tsodikov OV, Hura GL, Song W, Cotner EA, Classen S, Tomkinson AE, Tainer JA, Ellenberger T. A flexible interface between DNA ligase and PCNA supports conformational switching and efficient ligation of DNA. Mol Cell. 2006 Oct 20;24(2):279-91. PMID:17052461 doi:10.1016/j.molcel.2006.08.015

Elevated expression of DNA ligase I in human cancers., Sun DY, Urrabaz R, Nguyen M, Marty J, Stringer S, Cruz E, Medina-Gundrum L, Weitman S., Clinical Cancer Research. 2001; 7(12):4143-4148.
Replication failure, genome instability, and increased cancer susceptibility in mice with a point mutation in the DNA ligase I gene., Harrison C, Ketchen AM, Redhead NJ, O'Sullivan MJ, Melton DW., Cancer Research. 2002; 62(14):4065-4074.