# XRCC6

## Overview
The XRCC6 gene encodes the Ku70 protein, a crucial component of the DNA repair machinery in eukaryotic cells. Ku70, in conjunction with Ku80, forms the Ku heterodimer, which is integral to the non-homologous end joining (NHEJ) pathway, a primary mechanism for repairing DNA double-strand breaks. This protein complex is characterized by its ability to bind DNA ends with high affinity, facilitating the repair process by aligning DNA ends and recruiting other essential repair proteins. Beyond its role in DNA repair, Ku70 is involved in telomere maintenance, interacting with proteins such as hTERT and SIRT1 to protect chromosome termini. The XRCC6 gene has been implicated in various clinical conditions, with certain polymorphisms linked to increased cancer susceptibility, underscoring its significance in genomic stability and disease prevention (Kim2011Telomere; Bau2011Role; Walker2001Structure).

## Structure
The XRCC6 gene encodes the Ku70 protein, which forms a heterodimer with Ku80, known as the Ku complex. This complex plays a crucial role in the non-homologous end joining (NHEJ) pathway for DNA double-strand break repair. The Ku70 protein has a three-domain topology: an N-terminal von Willebrand Factor type A domain (VWA), a central Ku core region, and a C-terminal arm domain (Ku_C) (Bladen2007Expression; Walker2001Structure). The SAP domain, also present in Ku70, is involved in DNA binding and contributes to subunit-specific functions (Bladen2007Expression).

The Ku70/Ku80 heterodimer forms a ring-like structure that encircles DNA, allowing high-affinity binding to DNA ends without sequence specificity. This structure is characterized by a central β-barrel domain that forms the DNA-binding site, with Ku70 positioned proximal to the DNA end (Walker2001Structure). The heterodimer's stability is supported by β-hairpins, and its DNA-binding site is asymmetrical, contributing differently to the structure (Walker2001Structure).

Post-translational modifications, such as phosphorylation, can influence the function of Ku70, affecting its role in DNA repair processes (Frost2017The).

## Function
The XRCC6 gene encodes the Ku70 protein, which is a critical component of the Ku heterodimer, formed with Ku80. This heterodimer plays a vital role in the non-homologous end joining (NHEJ) pathway, a major mechanism for repairing DNA double-strand breaks (DSBs) in eukaryotic cells. The Ku70/Ku80 complex binds to DNA ends at DSBs, facilitating their alignment and making them accessible for further processing by enzymes involved in fill-in synthesis, nucleolytic processing, and ligation (Thacker2003The; Walker2001Structure). This process is essential for maintaining genomic stability and preventing carcinogenesis by ensuring proper DNA repair (Bau2011Role).

In addition to its role in DNA repair, XRCC6 is involved in telomere maintenance. The Ku complex interacts with several proteins, including hTERT, the catalytic subunit of telomerase reverse transcriptase, and SIRT1, a protein involved in DNA repair. This interaction is important for protecting chromosome termini and maintaining normal telomere length (Kim2011Telomere). Loss of either Ku subunit in human somatic cells results in cell death with substantial telomere loss, indicating the essential role of Ku in telomere maintenance (Kim2011Telomere).

## Clinical Significance
Mutations and alterations in the XRCC6 gene, also known as Ku70, have been associated with increased susceptibility to various cancers. Specific single nucleotide polymorphisms (SNPs) in XRCC6, such as rs2267437, have been linked to higher risks of breast cancer, hepatocellular carcinoma, and renal cell carcinoma, particularly in Asian populations (Jia2015Association). The rs5751129 polymorphism is associated with decreased XRCC6 expression and an increased risk of cancer (Jia2015Association). In nasopharyngeal carcinoma, the XRCC6 promoter T-991C polymorphism is linked to increased risk, with TC and CC genotypes showing lower XRCC6 mRNA and protein expression levels compared to the TT genotype (Huang2015The).

XRCC6 polymorphisms also play a role in other conditions. The XRCC6 promoter T-991C polymorphism is associated with a higher risk of developing pterygium, a condition with cancer-like characteristics (Bau2011Role). These genetic variations may influence cancer susceptibility by affecting the DNA repair processes in which XRCC6 is involved, highlighting the gene's clinical significance in cancer risk assessment and potential therapeutic targeting (Bau2011Role).

## Interactions
XRCC6, also known as Ku70, is a key player in the non-homologous end joining (NHEJ) pathway for DNA double-strand break repair. It forms a heterodimer with Ku80 (XRCC5), which binds to DNA ends and recruits the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the DNA-PK complex. This complex is essential for the initial recognition and protection of DNA ends, facilitating their repair (Hammel2021X‐ray; Ramsden1998Ku; Bau2011Role).

Ku70 interacts with the adenovirus E1A protein, which affects the virus life cycle by localizing to viral replication centers and associating with the viral genome. This interaction is crucial for efficient viral replication and cell cycle progression during infection (Frost2017The).

Ku70 also interacts with other proteins involved in DNA repair, such as XRCC4 and DNA ligase IV, which are critical for the final ligation step in the NHEJ pathway. These interactions are important for maintaining genomic stability and preventing tumorigenesis (Thacker2003The; Fujii2017Potential). The Ku heterodimer's ability to bind DNA and recruit other repair proteins underscores its central role in the DNA damage response.


## References


[1. (Frost2017The) Jasmine Rae Frost, Oladunni Olanubi, Stephen Ka-Hon Cheng, Andrea Soriano, Leandro Crisostomo, Alennie Lopez, and Peter Pelka. The interaction of adenovirus e1a with the mammalian protein ku70/xrcc6. Virology, 500:11–21, January 2017. URL: http://dx.doi.org/10.1016/j.virol.2016.10.004, doi:10.1016/j.virol.2016.10.004. This article has 22 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.virol.2016.10.004)

[2. (Jia2015Association) Jing Jia, Juan Ren, Dongmei Yan, Long Xiao, and Ruifen Sun. Association between the xrcc6 polymorphisms and cancer risks: a systematic review and meta-analysis. Medicine, 94(1):e283, January 2015. URL: http://dx.doi.org/10.1097/md.0000000000000283, doi:10.1097/md.0000000000000283. This article has 21 citations and is from a peer-reviewed journal.](https://doi.org/10.1097/md.0000000000000283)

[3. (Walker2001Structure) John R. Walker, Richard A. Corpina, and Jonathan Goldberg. Structure of the ku heterodimer bound to dna and its implications for double-strand break repair. Nature, 412(6847):607–614, August 2001. URL: http://dx.doi.org/10.1038/35088000, doi:10.1038/35088000. This article has 898 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/35088000)

[4. (Thacker2003The) John Thacker and Małgorzata Z. Zdzienicka. The mammalian xrcc genes: their roles in dna repair and genetic stability. DNA Repair, 2(6):655–672, June 2003. URL: http://dx.doi.org/10.1016/s1568-7864(03)00062-4, doi:10.1016/s1568-7864(03)00062-4. This article has 92 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/s1568-7864(03)00062-4)

[5. (Kim2011Telomere) Sangkyu Kim, Xiuhua Bi, Malwina Czarny-Ratajczak, Jianliang Dai, David A. Welsh, Leann Myers, Michael A. Welsch, Katie E. Cherry, Jonathan Arnold, Leonard W. Poon, and S. Michal Jazwinski. Telomere maintenance genes sirt1 and xrcc6 impact age-related decline in telomere length but only sirt1 is associated with human longevity. Biogerontology, 13(2):119–131, October 2011. URL: http://dx.doi.org/10.1007/s10522-011-9360-5, doi:10.1007/s10522-011-9360-5. This article has 79 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s10522-011-9360-5)

[6. (Huang2015The) C.-Y. Huang, C.-W. Tsai, C.-M. Hsu, L.-C. Shih, W.-S. Chang, H.-A. Shui, and D.-T. Bau. The role of xrcc6/ku70 in nasopharyngeal carcinoma. International Journal of Oral and Maxillofacial Surgery, 44(12):1480–1485, December 2015. URL: http://dx.doi.org/10.1016/j.ijom.2015.06.008, doi:10.1016/j.ijom.2015.06.008. This article has 5 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ijom.2015.06.008)

[7. (Bladen2007Expression) Catherine L. Bladen, Sammy Navarre, William S. Dynan, and David J. Kozlowski. Expression of the ku70 subunit (xrcc6) and protection from low dose ionizing radiation during zebrafish embryogenesis. Neuroscience Letters, 422(2):97–102, July 2007. URL: http://dx.doi.org/10.1016/j.neulet.2007.05.045, doi:10.1016/j.neulet.2007.05.045. This article has 36 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.neulet.2007.05.045)

[8. (Bau2011Role) Da-Tian Bau, Chia-Wen Tsai, and Cheng-Nan Wu. Role of the xrcc5/xrcc6 dimer in carcinogenesis and pharmacogenomics. Pharmacogenomics, 12(4):515–534, April 2011. URL: http://dx.doi.org/10.2217/pgs.10.209, doi:10.2217/pgs.10.209. This article has 23 citations and is from a peer-reviewed journal.](https://doi.org/10.2217/pgs.10.209)

[9. (Hammel2021X‐ray) Michal Hammel and John A. Tainer. X‐ray scattering reveals disordered linkers and dynamic interfaces in complexes and mechanisms for <scp>dna</scp> double‐strand break repair impacting cell and cancer biology. Protein Science, 30(9):1735–1756, June 2021. URL: http://dx.doi.org/10.1002/pro.4133, doi:10.1002/pro.4133. This article has 17 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/pro.4133)

[10. (Ramsden1998Ku) D. A. Ramsden. Ku protein stimulates dna end joining by mammalian dna ligases: a direct role for ku in repair of dna double-strand breaks. The EMBO Journal, 17(2):609–614, January 1998. URL: http://dx.doi.org/10.1093/emboj/17.2.609, doi:10.1093/emboj/17.2.609. This article has 212 citations.](https://doi.org/10.1093/emboj/17.2.609)

[11. (Fujii2017Potential) Naoaki Fujii. Potential strategies to target protein–protein interactions in the dna damage response and repair pathways. Journal of Medicinal Chemistry, 60(24):9932–9959, July 2017. URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00358, doi:10.1021/acs.jmedchem.7b00358. This article has 7 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1021/acs.jmedchem.7b00358)