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Ku80 is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that, in humans, is encoded by the ''XRCC5''
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 ...
. Together,
Ku70 Ku70 is a protein that, in humans, is encoded by the ''XRCC6'' gene. Function Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway o ...
and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break
ends End, END, Ending, or variation, may refer to: End *In mathematics: **End (category theory) **End (topology) **End (graph theory) ** End (group theory) (a subcase of the previous) ** End (endomorphism) *In sports and games **End (gridiron football ...
and is required for 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 direc ...
(NHEJ) pathway of
DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...
. It is also required 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 ...
, which utilizes the NHEJ pathway to promote antigen diversity in the mammalian
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
. 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. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...
length maintenance and subtelomeric gene silencing. Ku was originally identified when patients with
systemic lupus erythematosus Lupus, technically known as 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. Commo ...
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. ...
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 stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...
hypermethylation of the
promoter region In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein ( mRNA), or can have a function in and ...
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) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to s ...
and nearby normal lung tissue, 25% of the tumors had loss of heterozygosity 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 functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence invol ...
. 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 naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear D ...
).


Clinical significance

A rare
microsatellite A microsatellite is a tract of repetitive DNA in which certain 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 organism's genome. ...
polymorphism in this gene is associated with cancer in patients of varying
radiosensitivity Radiosensitivity is the relative susceptibility of cells, tissues, organs or organisms to the harmful effect of ionizing radiation. Cells types affected Cells are least sensitive when in the S phase, then the G1 phase, then the G2 phase, and ...
.


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).


Interactions

Ku80 has been shown to
interact Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...
with: *
DNA-PKcs DNA-dependent protein kinase, catalytic subunit, also known as DNA-PKcs, is an enzyme that in humans is encoded by the gene designated as ''PRKDC'' or ''XRCC7''. DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family. ...
, * GCN5L2, *
Ku70 Ku70 is a protein that, in humans, is encoded by the ''XRCC6'' gene. Function Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway o ...
, *
NCOA6 Nuclear receptor coactivator 6 is a protein that in humans is encoded by the ''NCOA6'' gene. Function The protein encoded by this gene is a transcriptional coactivator that can interact with nuclear hormone receptors to enhance their transcrip ...
, * PCNA, * POU2F1, * TERF2IP, * Telomerase reverse transcriptase, * Tyrosine kinase 2, and *
Werner syndrome ATP-dependent helicase Werner may refer to: People * Werner (name), origin of the name and people with this name as surname and given name Fictional characters * Werner (comics), a German comic book character * Werner Von Croy, a fictional character in the ''Tomb Ra ...
.


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