DNA ligase 4 is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
that in humans is encoded by the LIG4
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
Function
The protein encoded by this gene is an
ATP
ATP may refer to:
Companies and organizations
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-dependent
DNA ligase
DNA ligase is a specific type of enzyme, a ligase, () that facilitates the joining of DNA strands together by catalyzing the formation of a phosphodiester bond. It plays a role in repairing single-strand breaks in duplex DNA in living org ...
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. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...
pathway of double-strand break repair. It is also essential for
V(D)J recombination
V(D)J recombination 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 of antibodies/immunoglobulins and T cell re ...
. 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
LIG4 syndrome (also known as Ligase IV syndrome) is an extremely rare condition caused by mutations in the DNA Ligase IV (LIG4) gene. Some mutations in this gene are associated with a resistance against multiple myeloma and Severe Combined Immunod ...
. 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. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...
(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
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with
XRCC4 via its
BRCT domain
BRCA1 C Terminus (BRCT) domain is a family of evolutionarily related proteins. It is named after the C-terminal domain of BRCA1, a DNA-repair protein that serves as a marker of breast cancer susceptibility.
The BRCT domain is found predominan ...
.
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