Download Gene Section XRCC6 (X ray repair complementing defective

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
XRCC6 (X-ray repair complementing defective
repair in Chinese hamster cells 6)
Sabina Pucci, Maria Josè Zonetti
Lab of Molecular Pathology, Dept of Biopathology, University of Rome "Tor Vergata", Via Montpellier,
00133 Rome, Italy (SP, MJZ)
Published in Atlas Database: June 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/XRCC6ID246ch22q13.html
DOI: 10.4267/2042/44987
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Localisation
Identity
Ku was originally reported to be a nuclear protein,
consistent with its functions as a subunit of DNA-PK
involved in DNA double strand breaks repair.
However, several studies have revealed the cytoplasmic
or cell surface localization of Ku proteins in various
cell types (Prabhakar et al., 1990). Recently, it has been
demonstrated that the shift from the nucleus to the
cytoplasm of the Ku70/Ku80 proteins in tumor cells
could represents a mechanism to inhibit cell death
through the Ku70-Bax-sCLU interactions, giving rise
to a new chemoresistant clone with a more aggressive
phenotype.
Other names: CTC75, CTCBF, G22P1, KU70, ML8,
TLAA
HGNC (Hugo): XRCC6
Location: 22q13.2
DNA/RNA
Description
The KU70 gene is composed of 13 exons.
Transcription
2156 bp mRNA.
Function
Protein
Ku is a heterodimeric protein composed of two
subunits with molecular weight of 70 and 86 kDa. Ku
forms a complex with the DNA-dependent protein
kinase catalytic subunit (DNA-PKcs) to form the full
DNA-dependent protein kinase, DNA-PK, consisting
of 470 kDa and required for the non-homologous end
joining (NHEJ) pathway of DNA repair. The Ku
heterodimer binds the ends of various types of DNA
discontinuity, and is involved in the repair of DNA
breaks caused by an incorrect DNA replication, V(D)J
recombination, physiological oxidations, ionizing
irradiation, and some chemotherapeutic drug effects
(Featherstone and Jackson, 1999).
Description
The Ku70 protein is 609 amino acid long and its
molecular weight is 69.8 kDa. It is composed of 3
domains: an amino (N) amino-terminal alpha/beta
domain, a central beta-barrel domain and a helical Cterminal arm (Rivera-Calzada et al., 2007). The Cterminal region consists of a 5 kDa SAP domain
(Ku70-SAP) which involved in DNA binding during
NHEJ reaction.
Expression
Ku70 is ubiquitously expressed. Changes in Ku70
expression correlated to a pathological state.
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XRCC6 (X-ray repair complementing defective repair in Chinese hamster cells 6)
Pucci S, Zonetti MJ
Ku70/80-CLU-Bax interactions. (A) Bax is localized inactive in the cytoplasm in normal, undamaged cell interacting with the Ku70
protein C-terminus. sCLU stabilizes the Ku70-Bax interaction in the cytoplasm acting as cytoprotectant. (B) After DNA damage inducing
DNA double-strand breaks repair (UV treatment, ionizing radiation, etc.) Ku70 allows the translocation of Bax to the mitochondria
inducing apoptosis (Mazzarelli et al., 2009).
The principal role of Ku proteins is to take care of the
homeostasis of the genome being involved in telomere
maintenance, specific gene transcription, DNA
replication, cell-cycle regulation and regulation of
apoptosis induction. Ku70 has been shown to bind to
the pro-apoptotic protein BAX in the cytoplasm in
normal, undamaged cell. After DNA damage inducing
DNA double-strand breaks repair (UV treatment,
ionizing radiation, etc.) Ku70 allows the translocation
of Bax to the mitochondria leading to the release of
death-promoting factors, such as cytochrome c, in the
cytoplasmic compartment.
In normal cells, after an irreversible cell damage, nCLU
cooperates with Ku70 to induce apoptotic death,
activating the translocation of Bax to mitochondria
whereas the sCLU protein stabilizes the Ku70-Bax
interaction in the cytoplasm acting as cytoprotectant.
The Ku70-Bax-sCLU interaction in the cytoplasm
seems to play an important role in cell survival
pathways and in cell death escape, that in pathological
condition could lead to the survival of the aberrant cell
clone. Overall, the dynamic interactions among CLU,
Ku70, and Bax seems to have an important role in both
tumor insurgence and its progression (Pucci et al.,
2009a; Pucci et al., 2009b).
Ku70 and Ku80 are related to tumor progression in
colon cancer. DNA repair is inhibited in high
infiltrative colon carcinoma by Ku80 loss and Ku70
cell compartment shift (from the nucleus to the
cytoplasm).
Moreover in colorectal carcinoma was demonstrated a
very important role of Ku70 expression, localization,
and physical interaction with CLU and Bax. In fact the
Ku70-CLU-Bax colocalization in the cytoplasm and an
increase in Ku70-CLU-Bax binding were observed in
highly aggressive human colon cancer (Pucci et al.,
2004; Pucci et al., 2009c), confirming that these
interactions regulate the Bax-dependent cell death.
Breast cancer
Note
Experimental data further reported an inactivation of
Ku DNA-binding activity, essential for genomic
stability in breast and in bladder carcinomas. A
dysfunction of this protective activity let the aberrant
cell clone growing. In highly infiltrative and metastatic
tumors of the breast and bladder, the impaired DNArepair activity is due to the loss of Ku86 (Pucci et al.,
2001) and to the Ku70 shifting from the nucleus to the
cytoplasm. The shift from the nucleus to the cytoplasm
of the Ku70/80 proteins in tumor cells could represents
a mechanism to inhibit cell death through the
cooperative interaction with sCLU, giving rise to a new
chemoresistant clone with a more aggressive
phenotype.
Implicated in
Colon cancer
Note
The colon cancer expression and the localization of
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3)
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Pucci S, Zonetti MJ
Tumor-specific modulation of Ku70/80 in human colon cancer. Ku70 staining was strongly positive in the nuclei of normal mucosa. In
node-negative carcinomas (pT3N0) Ku70 expression slightly decreased and it localized mainly in the nucleus. In node-positive
carcinomas (pT3N1) Ku70 staining was distributed mainly in cytoplasm. The expression of Ku86 was positive in the nuclei of control
tissues (normal mucosa). Nuclear Ku86 expression was strongly decreased in node-negative tumors (pT3N0). No staining for Ku86 was
found in the nucleus or in the cytoplasm of node-positive carcinomas (pT3N1).
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Ku70-Bax-CLU pathological interaction. Apoptosis escaping. The shift of clusterin forms production, the loss of Ku80, and the
cytoplasmic relocalization of Ku70 are related to cell death inhibition and cancer progression.
Mazzarelli P, Pucci S, Spagnoli LG. CLU and colon cancer.
The dual face of CLU: from normal to malignant phenotype.
Adv Cancer Res. 2009;105:45-61
References
Prabhakar BS, Allaway GP, Srinivasappa J, Notkins AL. Cell
surface expression of the 70-kD component of Ku, a DNAbinding nuclear autoantigen. J Clin Invest. 1990
Oct;86(4):1301-5
Pucci S, Bonanno E, Sesti F, Mazzarelli P, Mauriello A, Ricci
F, Zoccai GB, Rulli F, Galatà G, Spagnoli LG. Clusterin in
stool: a new biomarker for colon cancer screening? Am J
Gastroenterol. 2009 Nov;104(11):2807-15
Featherstone C, Jackson SP. Ku, a DNA repair protein with
multiple cellular functions? Mutat Res. 1999 May 14;434(1):315
Pucci S, Mazzarelli P, Nucci C, Ricci F, Spagnoli LG. CLU "in
and out": looking for a link. Adv Cancer Res. 2009;105:93-113
Pucci S, Mazzarelli P, Rabitti C, Giai M, Gallucci M, Flammia
G, Alcini A, Altomare V, Fazio VM. Tumor specific modulation
of KU70/80 DNA binding activity in breast and bladder human
tumor biopsies. Oncogene. 2001 Feb 8;20(6):739-47
Pucci S, Mazzarelli P, Sesti F, Boothman DA, Spagnoli LG.
Interleukin-6 affects cell death escaping mechanisms acting on
Bax-Ku70-Clusterin interactions in human colon cancer
progression. Cell Cycle. 2009 Feb 1;8(3):473-81
Pucci S, Bonanno E, Pichiorri F, Angeloni C, Spagnoli LG.
Modulation of different clusterin isoforms in human colon
tumorigenesis. Oncogene. 2004 Mar 25;23(13):2298-304
This article should be referenced as such:
Pucci S, Zonetti MJ. XRCC6 (X-ray repair complementing
defective repair in Chinese hamster cells 6). Atlas Genet
Cytogenet Oncol Haematol. 2011; 15(3):293-296.
Rivera-Calzada A, Spagnolo L, Pearl LH, Llorca O. Structural
model of full-length human Ku70-Ku80 heterodimer and its
recognition of DNA and DNA-PKcs. EMBO Rep. 2007
Jan;8(1):56-62
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(3)
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