Molecular cloning, genomic characterization and over-expression of a novel gene, XRRA1, identified from human colorectal cancer cell HCT116Clone2_XRR and macaque testis

Mesak, Felix; Osada, Naoki; Hashimoto, Katsuyuki; Liu, Qing Y.; Ng, Cheng E.

doi:10.1186/1471-2164-4-32

Cited by 13 publications

(10 citation statements)

References 29 publications

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“…Up-regulated expression of XRRA1 has been linked to reduced capacity for DNA damage repair in human cell lines. 36 Overall, Gene Ontology classification based on the molecular function of these 2629 genes indicated that the set was enriched for oxidoreductase and dehydrogenase activity but also for KRAB domain containing zinc finger transcription factors (Table 1). The data were very similar when 1-mb windows were used instead.…”

Section: Resultsmentioning

confidence: 99%

Expression Quantitative Trait Loci Analysis Identifies Associations Between Genotype and Gene Expression in Human Intestine

Kabakchiev

Silverberg

2013

Gastroenterology

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BACKGROUND & AIMS Genome-wide association studies have greatly increased our understanding of intestinal disease. However, little is known about how genetic variations result in phenotypic changes. Some polymorphisms have been shown to modulate quantifiable phenotypic traits; these are called quantitative trait loci. Quantitative trait loci that affect levels of gene expression are called expression quantitative trait loci (eQTL), which can provide insight into the biological relevance of data from genome-wide association studies. We performed a comprehensive eQTL scan of intestinal tissue. METHODS Total RNA was extracted from ileal biopsy specimens and genomic DNA was obtained from whole-blood samples from the same cohort of individuals. Cis- and trans-eQTL analyses were performed using a custom software pipeline for samples from 173 subjects. The analyses determined the expression levels of 19,047 unique autosomal genes listed in the US National Center for Biotechnology Information database and more than 580,000 variants from the Single Nucleotide Polymorphism database. RESULTS The presence of more than 15,000 cis- and trans-eQTL was detected with statistical significance. eQTL associated with the same expression trait were in high linkage disequilibrium. Comparative analysis with previous eQTL studies showed that 30% to 40% of genes identified as eQTL in monocytes, liver tissue, lymphoblastoid cell lines, T cells, and fibroblasts are also eQTL in ileal tissue. Conversely, most of the significant eQTL have not been previously identified and could be tissue specific. These are involved in many cell functions, including division and antigen processing and presentation. Our analysis confirmed that previously published cis-eQTL are single nucleotide polymorphisms associated with inflammatory bowel disease: rs2298428/UBE2L3, rs1050152/SLC22A4, and SLC22A5. We identified many new associations between inflammatory bowel disease susceptibility loci and gene expression. CONCLUSIONS eQTL analysis of intestinal tissue supports findings that some eQTL remain stable across cell types, whereas others are specific to the sampled location. Our findings confirm and expand the number of known genotypes associated with expression and could help elucidate mechanisms of intestinal disease.

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Section: Resultsmentioning

confidence: 99%

Expression Quantitative Trait Loci Analysis Identifies Associations Between Genotype and Gene Expression in Human Intestine

Kabakchiev

Silverberg

2013

Gastroenterology

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“…It is widely known that cycle arrest results in the inhibition of cell proliferation. Cyclin D1 and cyclin A are regulated by p21 to influence the cell cycle and cell proliferation [ 1 , 3 ]. Overexpression of cyclin A and cyclin E could induce G 1 arrest [ 4 ], whereas p21 mediated G2-phase cell cycle arrest [ 5 ].…”

Section: Resultsmentioning

confidence: 99%

“…Human XRRA1 cDNA is 1987 nt long and encodes a protein of 559 aa. Mesak et al [ 1 ] detected XRRA1 expression in normal tissues/organs and cells, as well as in various cancer cell types (such as breast cancer, glioma, melanoma, lung cancer, and neuroblastoma) by RT-PCR and found that XRRA1 was present in all cell types, although the expression level was variable. To understand further the possible function of the XRRA1 gene, we overexpressed XRRA1 in six different tumor cell lines and found significantly increased cell proliferation compared with the control.…”

Section: Discussionmentioning

confidence: 99%

“…DNA repair dysfunction is not only closely related to tumor development but also related to chemotherapy drug resistance. X-ray radiation resistance associated 1 (XRRA1) [ 1 ] is a new gene containing 11 exons that encodes a protein of 559 amino acids containing a leucine-rich repeat sequence, PEST sequence, and two tyrosine phosphorylation sites. The amino acid sequence of XRRA1 has great conservation between species.…”

Section: Introductionmentioning

confidence: 99%

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XRRA1 Targets ATM/CHK1/2-Mediated DNA Repair in Colorectal Cancer

Wang

Guo

Xia

et al. 2017

BioMed Research International

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X-ray radiation resistance associated 1 (XRRA1) has been found to regulate the response of human tumor and normal cells to X-radiation (XR). Although XRRA1 overexpression is known to be involved in cancer cell response to XR, there are no reports about whether the expression of XRRA1 in tumors can adjust radioresistance. It is widely known that cell cycle arrest could cause radioresistance. We found that blocked XRRA1 expression could lead to cell cycle G2/M arrest by the regulation of cyclin A, cyclin E, and p21 proteins in colorectal cancer (CRC) and expression of XRRA1 reduced cell cycle arrest and increased cell proliferation in CRC. However, whether regulation of the cell cycle by XRRA1 can influence radioresistance is poorly characterized. Correspondingly, DNA repair can effectively lead to radioresistance. In our study, when cancer cells were exposed to drugs and ionizing radiation, low expression of XRRA1 could increase the phosphorylation of DNA repair pathway factors CHK1, CHK2, and ATM and reduce the expression of γ-H2AX, which is believed to participate in DNA repair in the nucleus. Crucially, our results identify a novel link between XRRA1 and the ATM/CHK1/2 pathway and suggest that XRRA1 is involved in a DNA damage response that drives radio- and chemoresistance by regulating the ATM/CHK1/2 pathway.

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“…MIR4696 encodes a microRNA, which are involved in post-translational gene expression regulation 51 . The XRRA1 gene product is believed to regulate cell response to X-radiation exposure; the lead SNP in the EA group analysis falls within the XRRA1 gene 52 . SPCS2 encodes a subunit of the microsomal signal peptidase complex, which removes signaling peptides from newly-formed proteins as they move to the endoplasmic reticulum 53 .…”

Section: Resultsmentioning

confidence: 99%

Unfolding of hidden white blood cell count phenotypes for gene discovery using latent class mixed modeling

et al. 2018

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Resting-state white blood cell (WBC) count is a marker of inflammation and immune system health. There is evidence that WBC count is not fixed over time and there is heterogeneity in WBC trajectory that is associated with morbidity and mortality. Latent class mixed modeling (LCMM) is a method that can identify unobserved heterogeneity in longitudinal data and attempts to classify individuals into groups based on a linear model of repeated measurements. We applied LCMM to repeated white blood cell (WBC) count measures derived from electronic medical records of participants of the National Human Genetics Research Institute (NHRGI) electronic MEdical Record and GEnomics (eMERGE) network study, revealing two WBC count trajectory phenotypes. Advancing these phenotypes to GWAS, we found genetic associations between trajectory class membership and regions on chromosome 1p34.3 and chromosome 11q13.4. The chromosome 1 region contains CSF3R, which encodes the granulocyte colony stimulating factor receptor. This protein is a major factor in neutrophil stimulation and proliferation. The association on chromosome 11 contain genes RNF169 and XRRA1; both involved in the regulation of double strand break DNA repair.

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Molecular cloning, genomic characterization and over-expression of a novel gene, XRRA1, identified from human colorectal cancer cell HCT116Clone2_XRR and macaque testis

Cited by 13 publications

References 29 publications

Expression Quantitative Trait Loci Analysis Identifies Associations Between Genotype and Gene Expression in Human Intestine

Expression Quantitative Trait Loci Analysis Identifies Associations Between Genotype and Gene Expression in Human Intestine

XRRA1 Targets ATM/CHK1/2-Mediated DNA Repair in Colorectal Cancer

Unfolding of hidden white blood cell count phenotypes for gene discovery using latent class mixed modeling

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