Ku80
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Ku80 is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that, in humans, is encoded by the ''XRCC5''
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 ...
. Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
double-strand break ends and is required for 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 ...
(NHEJ) pathway of
DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...
. It is also required 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 ...
, which utilizes the NHEJ pathway to promote antigen diversity in the mammalian
immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
. In addition to its role in NHEJ, Ku is required for
telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes (see #Sequences, Sequences). Telomeres are a widespread genetic feature most commonly found in eukaryotes. In ...
length maintenance and subtelomeric gene silencing. Ku was originally identified when patients with
systemic lupus erythematosus Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...
were found to have high levels of
autoantibodies An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies. Pr ...
to the protein.


Nomenclature

Ku80 has been referred to by several names including: * Lupus Ku autoantigen protein p80 * ATP-dependent DNA helicase 2 subunit 2 * X-ray repair complementing defective repair in Chinese hamster cells 5 * X-ray repair cross-complementing 5 (XRCC5)


Epigenetic repression

The protein expression level of Ku80 can be repressed by
epigenetic In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...
hypermethylation of the promoter region of gene ''XRCC5'' which encodes Ku80. In a study of 87 matched pairs of primary tumors of
non-small-cell lung carcinoma Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...
and nearby normal lung tissue, 25% of the tumors had
loss of heterozygosity In genetics, loss of heterozygosity (LOH) is a type of genetic abnormality in diploid organisms in which one copy of an entire gene and its surrounding chromosomal region are lost. Since diploid cells have two copies of their genes, one from each ...
at the XRCC5 locus and a similar percentage of tumors had hypermethylation of the promoter region of ''XRCC5''. Low protein expression of Ku80 was significantly associated with low mRNA expression and with ''XRCC5'' promoter hypermethylation but not with LOH of the gene.


Senescence

Mouse mutants with homozygous defects in Ku80 experience an early onset of
senescence Senescence () or biological aging is the gradual deterioration of Function (biology), functional characteristics in living organisms. Whole organism senescence involves an increase in mortality rate, death rates or a decrease in fecundity with ...
. Ku80(-/-) mice exhibit aging-related pathology (osteopenia, atrophic skin, hepatocellular degeneration, hepatocellular inclusions, hepatic hyperplastic foci and age-specific mortality). Furthermore, Ku80(-/-) mice exhibit severely reduced lifespan and size. Loss of only a single Ku80 allele in Ku(-/+) heterozygous mice causes accelerated aging in skeletal muscle, although post natal growth is normal. An analysis of the level of Ku80 protein in human, cow, and mouse indicated that Ku80 levels vary dramatically between species, and that these levels are strongly correlated with species longevity. These results suggest that the NHEJ pathway of DNA repair mediated by Ku80 plays a significant role in repairing double-strand breaks that would otherwise cause early senescence (see
DNA damage theory of aging The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of DNA damage (naturally occurring), naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although ...
).


Clinical significance

A rare
microsatellite A microsatellite is a tract of repetitive DNA in which certain Sequence motif, DNA motifs (ranging in length from one to six or more base pairs) are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organ ...
polymorphism in this gene is associated with cancer in patients of varying radiosensitivity.


Deficiency in cancer

A deficiency in expression of a DNA repair gene increases the risk for cancer (see Deficient DNA repair in carcinogenesis). Ku80 protein expression was found to be deficient in melanoma. In addition, low expression of Ku80 was found in 15% of adenocarcinoma type and 32% of squamous cell type non-small cell lung cancers, and this was correlated with hypermethylation of the ''XRCC5'' promoter. Ku80 appears to be one of 26 different DNA repair proteins that are epigenetically repressed in various cancers (see
Cancer epigenetics Cancer epigenetics is the study of epigenetics, epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mecha ...
).


Interactions

Ku80 has been shown to interact with: * DNA-PKcs, * GCN5L2, * Ku70, * NCOA6, *
PCNA Proliferating cell nuclear antigen (PCNA) is a DNA clamp that acts as a processivity factor for DNA polymerase delta, DNA polymerase δ in eukaryotic cell (biology), cells and is essential for replication. PCNA is a homotrimer and achieves its ...
, * POU2F1, * TERF2IP, *
Telomerase reverse transcriptase Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex. ...
, * Tyrosine kinase 2, and *
Werner syndrome ATP-dependent helicase Werner syndrome ATP-dependent helicase, also known as DNA helicase, RecQ-like type 3, is an enzyme that in humans is encoded by the ''WRN'' gene. WRN is a member of the RecQ Helicase family. Helicase enzymes generally unwind and separate double- ...
.


References


Further reading

* * * * * * * * * * * * * * * * * * * *


External links


PDBe-KB
provides an overview of all the structure information available in the PDB for Human X-ray repair cross-complementing protein 5 {{PDB Gallery, geneid=7520