DNA ligase 4 also DNA ligase IV, is an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''LIG4''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Function
DNA ligase 4 is an
ATP-dependent
DNA ligase that joins double-strand breaks during the
non-homologous end joining
Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair ...
pathway of double-strand break repair. It is also essential for
V(D)J recombination
V(D)J recombination (variable–diversity–joining rearrangement) is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire ...
. Lig4 forms a complex with
XRCC4, and further interacts with the DNA-dependent protein kinase (DNA-PK) and
XLF/Cernunnos, which are also required for NHEJ. The crystal structure of the Lig4/XRCC4 complex has been resolved.
Defects in this gene are the cause of
LIG4 syndrome. The yeast homolog of Lig4 is Dnl4.
LIG4 syndrome
In humans, deficiency of DNA ligase 4 results in a clinical condition known as
LIG4 syndrome. This syndrome is characterized by cellular radiation sensitivity, growth retardation, developmental delay, microcephaly, facial dysmorphisms, increased disposition to leukemia, variable degrees of immunodeficiency and reduced number of blood cells.
Haematopoietic stem cell aging
Accumulation of DNA damage leading to stem cell exhaustion is regarded as an important aspect of aging.
Deficiency of lig4 in pluripotent stem cells impairs
Non-homologous end joining
Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair ...
(NHEJ) and results in accumulation of DNA double-strand breaks and enhanced apoptosis.
Lig4 deficiency in the mouse causes a progressive loss of haematopoietic stem cells and bone marrow cellularity during aging.
The sensitivity of haematopoietic stem cells to lig4 deficiency suggests that lig4-mediated NHEJ is a key determinant of the ability of stem cells to maintain themselves against physiological stress over time.
Interactions
LIG4 has been shown to
interact with
XRCC4 via its
BRCT domain.
This interaction stabilizes LIG4 protein in cells; cells that are deficient for
XRCC4, such as XR-1 cells, have reduced levels of LIG4.
Mechanism
LIG4 is an ATP-dependent DNA ligase. LIG4 uses ATP to adenylate itself and then transfers the AMP group to the 5' phosphate of one DNA end. Nucleophilic attack by the 3' hydroxyl group of a second DNA end and release of AMP yield the ligation product. Adenylation of LIG4 is stimulated by
XRCC4 and
XLF.
References
Further reading
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{{PDB Gallery, geneid=3981
DNA repair