Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
A novel variable number of tandem repeats (VNTR) polymorphism containing Sp1 binding elements in the promoter of XRCC5 is a risk factor for human bladder cancer
Introduction
It is generally believed that cancer is the result of a series of genetic alterations leading to progressive disorders in the normal mechanisms controlling cellular growth, differentiation, death, and genomic instability. The cellular capacity to repair genetic injury and to maintain genomic stability by means of a variety of DNA repair mechanisms is essential in preventing tumor initiation and progression. Bladder cancer is common worldwide. In 2000, there were 340,000 newly diagnosed bladder cancer cases and 130,000 related deaths; 70% of the cases occurred in men [1]. Associated with the risk of bladder cancer are environmental factors, such as chemical carcinogens, including polycyclic aromatic hydrocarbons, aromatic amines, and N-nitroso compounds; some anticancer drugs; and reactive oxygen species [2], [3], [4]. Although many people are exposed to these risk factors, only a few develop bladder cancer, suggesting that there is an individual variation in susceptibility to exposure-related bladder carcinogenesis.
Because damage caused by DNA double-strand breaks (DSB) leads to loss or rearrangement of genomic material, the pathways for repairing the damage are important for genomic stability [5]. If DNA DSB damage remains unrepaired or is inaccurately repaired, mutations and/or chromosomal aberrations are induced, and these may result in cancer or cell death [6]. To combat the effects of DNA DSB damage, eukaryotic cells have evolved non-homologous end joining (NHEJ) and homologous recombination processes to mediate repair mechanisms. In higher eukaryotic cells, NHEJ, also known as illegitimate recombination, is predominant [7], [8], [9], [10].
The human X-ray repair cross-complementing 5 (XRCC5) gene, which is also named Ku80 or Ku86, is on chromosome 2q35 [11] and encodes the XRCC5 protein. As one of three subunits of a DNA-dependent protein kinase, XRCC5 contributes to NHEJ, which is involved in maintaining genomic integrity. Defects in XRCC5 may induce deficiencies in DNA DSB repair, leading to growth retardation, chromosomal aberrations, hypersensitivity to ionizing radiation, and severe combination immune deficiency due to severely impaired V(D)J recombination [12], [13]. Although loss of XRCC5 can result in instability of the genome and in increased development of tumors, overexpression of XRCC5 is also associated with the progression of bladder cancer, gastric cancer, and breast cancer [14], [15], [16].
The proximate promoter of XRCC5 contains seven copies of cis elements, which are essential for basal expression and are subject to CpG methylation [17]. Recently, we identified a novel variable number of tandem repeats (VNTR) polymorphism (rs 6147172) located in this functional region of the XRCC5 promoter. This polymorphism contains three different alleles, which are two 21 nucleotides repeats (2R) (−201 to −160 relative to the initiation of transcription), one 21 nucleotides repeat (1R) (−180 to −160), and a zero repeat (0R). Computer analysis (AliBaba) predicted that this VNTR polymorphism, which includes a variable number of Sp1-binding motifs, might affect the transcriptional activity of XRCC5 and therefore lead to a phenotypic variation that could affect susceptibility to cancer. To test this hypothesis, we examined the function of this VNTR polymorphism and evaluated the association between its genotypes and susceptibility of a Chinese population to bladder cancer.
Section snippets
Study subjects
The subject recruitment for this study has been described previously [18]. In brief, 213 patients with a confirmed histologic diagnosis of bladder cancer and 235 cancer-free control subjects were recruited from The First Affiliated Hospital, Nanjing Medical University between January 2003 and November 2004 without any restriction of age and sex. All cases were patients newly diagnosed with histologically confirmed transitional cell carcinoma of the bladder. The exclusion criteria included
A schematic diagram depicting the VNTR polymorphism in promoter of XRCC5
In Fig. 1, a schematic diagram depicts the VNTR polymorphism in the promoter of XRCC5. There are three different alleles, one including the 42 nucleotides in the rectangular box, which is composed of two 21-nucleotide repeat elements (2R). Another contains only one 21-nucleotide repeat in the rectangular box (1R). The other includes no repeat element, i.e., 42 nucleotides in the rectangular box absent (0R). For this sequence, +1 and a bent arrow designate the site for initiation of
Discussion
In the present study, we examined the functional significance of a VNTR polymorphism in the XRCC5 promoter and, in a hospital-based case–control study, evaluated the impact of this polymorphism on the risk of the bladder cancer in a southeastern Chinese population.
The VNTR polymorphism in the promoter of XRCC5 was detected in a Chinese population using PCR and confirmed with sequencing. There were three different alleles, 2R, 1R, and 0R. Following the VNTR polymorphism sequences in the XRCC5
Acknowledgements
We are grateful to Dr. Donald L. Hill (University of Alabama at Birmingham, USA) for editing this paper. This work was supported in part by the National Natural Science Foundation of China (30571541), the Natural Science Foundation of Jiangsu Province (BK2006233, BK2005161), the Medicine Foundation of Jiangsu Province (H200506), and the Creative Science Foundation of Nanjing Medical University (CX2004002).
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2019, Journal of Trace Elements in Medicine and BiologyAssociation between VNTR polymorphism in promoter region of XRCC5 and susceptibility to acute lymphoblastic leukemia risk
2019, Gene ReportsCitation Excerpt :In addition, the number of tandem repeats at the promoter region of XRCC5 is associated with mRNA level expression (Rajaei et al., 2013). There are a few reports on the relationship between polymorphisms of the XRCC5 and susceptibility to sporadic bladder, chronic myeloid leukemia, esophagus, liver, gastric, and breast cancers (Saadat et al., 2015; Wang et al., 2008; Gorre et al., 2014b; Dong et al., 2007; Li et al., 2011; Yang et al., 2011; Rajaei et al., 2014). Nevertheless, no investigation was observed between the promoter region of the VNTR XRCC5 polymorphism and susceptibility to ALL cancer.
The single nucleotide polymorphism g.133A>C in the stearoyl CoA desaturase gene (SCD) promoter affects gene expression and quali-quantitative properties of river buffalo milk
2019, Journal of Dairy ScienceCitation Excerpt :The Sp1 motifs are well-known enhancer elements for the basal expression of many genes, including SCD, where they cover conserved promoter regions fundamental for gene expression (Keating et al., 2006; Pauciullo et al., 2012). Furthermore, these motifs often occur in clusters generated by variable number tandem repeats (VNTR; Fürbass et al., 2006; Wang et al., 2008). Their variability might regulate the transcription rate of the gene, as demonstrated for instance in other key genes involved in milk triacylglycerol synthesis or related to lipid droplet formation and secretion.
The novel allele (3R) of the VNTR polymorphism in the XRCC5 promoter region dramatically decreases the gene expression
2013, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Several genetic polymorphisms in the XRCC5 (X-ray repair cross-complementing 5; MIM: 194364) have been reported. A variable number of tandem repeats of a 21 bp (VNTR, rs. 6147172) polymorphism in the promoter region of XRCC5 has been reported [2]. This polymorphism has four alleles: 3R, 2R, 1R and 0R [3].
Introducing a novel allele for the polymorphism of variable number of tandem repeats in the promoter region of XRCC5
2012, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Previous reports for other genetic polymorphisms such as GSTM1, GSTT1, GSTO2, XRCC1, CC16 and GRIN1 [3,4,8–16], showed that the Iranian gene pool showed intermediate frequency in comparison with European Caucasians and Asians. Although no report from other countries (except for China and Iran) exist regarding the frequency of VNTR XRCC5 polymorphism [2,5, present study], it is suggested that the 3R allele might be present among Caucasian populations. Also it is suggested that the frequency of the 3R allele among European populations might be higher than its prevalence among the Iranian population.