Ku70

Ku70 is a heterodimeric protein made up of Ku70 and Ku80, which together form Ku. In humans, is encoded by the ''XRCC6'' gene. Ku70 plays a critical role in the DNA repair, maintenance and many other cellular processes.

Function

Together, Ku70 and Ku80 make up the Ku heterodimer form a quasi-symmetric structure, which encircles the double-stranded DNA. The DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) of the DNA repair pathway. It is also required for V(D)J recombination, which utilizes the NHEJ pathway to promote antigen diversity in the mammalian immune system. Ku70 is key for sensing and responding to cytosolic DNA, which is essential for the indication of infection.
Within the heterodimer, Ku70 specifically binds directly to broken ends of double-stranded DNA breaks, or DSBs. Then together, Ku70 and Ku80 will tightly form a ring-like structure around the DNA strand, preventing further degradation. These steps are essential for the success of non-homologous end joining.

The Ku70 subunit is located proximal to the DNA end. The Ku70 homodimer will stably bind 50 bp dsDNA substrate-forming complexes, allowing the DSBs to successfully enter the heterodimer, Ku's, central cavity. The Ku70 and Ku80 subunits can be expressed individually, however no DNA binding was observed from these isolated subunits. Lysine reside found in the Ku70 N-terminal domain is critical for the end processing functionality of the Ku heterodimer.

In addition to its role in NHEJ, Ku is also required for telomere length maintenance and subtelomeric gene silencing.

Ku was originally identified when patients with systemic lupus erythematosus were found to have high levels of autoantibodies to the protein.

Ku70 was also discovered to be an inhibitor of Bax-dependent signaling pathway. Suppression of Ku70 demonstrated the increase in Bax-dependent apoptosis. Interactions between Ku70 and Bax occurs in the C-terminus of Ku70 and the N-terminus of Bax. These specific interactions result in the cytosolic sequestration of Bax.

Aging

Mouse embryonic stem cells with homozygous Ku70 mutations, that is Ku70^−/− cells, have markedly increased sensitivity to ionizing radiation compared to heterozygous Ku70^+/− or wild-type Ku70^+/+ embryonic stem cells. Mutant mice deficient in Ku70 exhibit early aging. Using several specific criteria of aging, the mutant mice were found to display the same aging signs as control mice, but at a considerably earlier chronological age. These results suggest that reduced ability to repair DNA double-strand breaks causes early aging, and that the wild-type Ku70 gene plays an important role in longevity assurance. (Also see DNA damage theory of aging.)

Clinical

A mutation in this gene has been described in a set of 24 families with autism. While this is suggestive that this gene may play a role in the development of autism, further investigation is required.

Recent studies demonstrate that Ku proteins, when exactly balanced have the ability to act as a tumor suppressor gene. However, if there is an over-expression of Ku, it may act an oncoprotein. The presence of Ku of NHEJ in tumors affect the response to radiotherapy or chemotherapy, demonstrating the possibility that Ku has the potential to be used as a means to overcome resistance in cancer treatments.

Nomenclature

Ku70 has been referred to by several names including:
* Lupus Ku autoantigen protein p70
* ATP-dependent DNA helicase 2 subunit 1
* X-ray repair complementing defective repair in Chinese hamster cells 6
* X-ray repair cross-complementing 6 (XRCC6)

Interactions

Ku70 has been shown to interact with:

* CBX5,
* CHEK1,
* CREBBP,
* GCN5L2,
* HOXC4,
* Ku80,
* MRE11A,
* NCOA6,
* NCF4,
* PCNA,
* PTTG1,
* RPA2,
* TERF2,
* TERT
* VAV1, and
* WRN.

References

Further reading

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External links

PDBe-KB
provides an overview of all the structure information available in the PDB for Human X-ray repair cross-complementing protein 6

{{PDB Gallery, geneid=2547