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      A Non-Synonymous Single Nucleotide Polymorphism in the HJURP Gene Associated with Susceptibility to Hepatocellular Carcinoma among Chinese

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          Abstract

          Objective

          HJURP (Holliday Junction-Recognizing Protein) plays dual roles in DNA repair and in accurate chromosome segregation during mitosis. We examined whether the single nucleotide polymorphisms (SNPs) of HJURP were associated with the risk of occurrence of hepatocellular carcinoma (HCC) among chronic hepatitis B virus (HBV) carriers from well-known high-risk regions for HCC in China.

          Methods

          Twenty-four haplotype-tagging SNPs across HJURP were selected from HapMap data using the Haploview software. We genotyped these 24 SNPs using the using Sequenom's iPLEX assay in the Fusui population, consisting of 348 patients with HCC and 359 cancer-free controls, and further investigated the significantly associated SNP using the TaqMan assay in the Haimen population, consisting of 100 cases and 103 controls. The genetic associations with the risk of HCC were analyzed by logistic regression.

          Results

          We observed an increased occurrence of HCC consistently associated with A/C or C/C genotypes of the non-synonymous SNP rs3771333 compared with the A/A genotype in both the Fusui and Haimen populations, with a pooled odds ratio 1.82 (95% confidence interval, 1.33–2.49; P = 1.9 × 10 −4). Case-only analysis further indicated that carriers of the at-risk C allele were younger than those carrying the A/A genotype ( P = 0.0016). In addition, the expression levels of HJURP in C allele carriers were lower than that in A/A genotype carriers ( P = 0.0078 and 0.0010, for mRNA and protein levels, respectively).

          Conclusion

          Our findings suggest that rs3771333 in HJURP may play a role in mediating the susceptibility to HCC among Chinese.

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          Most cited references35

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          ATM activation by oxidative stress.

          The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.
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            Centromere-specific assembly of CENP-a nucleosomes is mediated by HJURP.

            The centromere is responsible for accurate chromosome segregation. Mammalian centromeres are specified epigenetically, with all active centromeres containing centromere-specific chromatin in which CENP-A replaces histone H3 within the nucleosome. The proteins responsible for assembly of human CENP-A into centromeric nucleosomes during the G1 phase of the cell cycle are shown here to be distinct from the chromatin assembly factors previously shown to load other histone H3 variants. Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURP. Recruitment of new CENP-A into nucleosomes at replicated centromeres is dependent on HJURP. Recognition by HJURP is mediated through the centromere targeting domain (CATD) of CENP-A, a region that we demonstrated previously to induce a unique conformational rigidity to both the subnucleosomal CENP-A heterotetramer and the corresponding assembled nucleosome. We propose HJURP to be a cell-cycle-regulated CENP-A-specific histone chaperone required for centromeric chromatin assembly.
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              HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres.

              The histone H3 variant CenH3, called CENP-A in humans, is central in centromeric chromatin to ensure proper chromosome segregation. In the absence of an underlying DNA sequence, it is still unclear how CENP-A deposition at centromeres is determined. Here, we purified non-nucleosomal CENP-A complexes to identify direct CENP-A partners involved in such a mechanism and identified HJURP. HJURP was not detected in H3.1- or H3.3-containing complexes, indicating its specificity for CENP-A. HJURP centromeric localization is cell cycle regulated, and its transient appearance at the centromere coincides precisely with the proposed time window for new CENP-A deposition. Furthermore, HJURP downregulation leads to a major reduction in CENP-A at centromeres and impairs deposition of newly synthesized CENP-A, causing mitotic defects. We conclude that HJURP is a key factor for CENP-A deposition and maintenance at centromeres.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 February 2016
                2016
                : 11
                : 2
                : e0148618
                Affiliations
                [1 ]State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China
                [2 ]National Engineering Research Center for Protein Drugs, Beijing, China
                [3 ]National Center for Protein Sciences Beijing, Beijing, China
                [4 ]Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
                [5 ]The Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
                [6 ]Department of Gastroenterology and Hepatology, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University, Nanjing, Jiangsu, China
                [7 ]Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, China
                [8 ]The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
                [9 ]Liver Cancer Institute at Fusui County, Guangxi, China
                [10 ]Disease Prevention and Control Center at Haimen County, Jiangsu, China
                Nanjing Medical University, CHINA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GZ HZ WX. Performed the experiments: WH YH. Analyzed the data: HZ WH YH XX. Contributed reagents/materials/analysis tools: WH HZ XX Y. Zhai SW Yang Li FM Yuanfeng Li ZW Y. Zhang XZ RL ZW YC Yongqiang Li XY HJ. Wrote the paper: WH HZ XX GZ. Critical review of manuscript: GZ HZ WX FH.

                Article
                PONE-D-15-23612
                10.1371/journal.pone.0148618
                4749235
                26863619
                a79fce64-7f0d-42ae-81a7-2fee3dd2e810
                © 2016 Huang et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 31 May 2015
                : 24 December 2015
                Page count
                Figures: 1, Tables: 4, Pages: 15
                Funding
                This work was supported by grants from the National Natural Science Foundation of China (No. 81125017, 81222027 and 81060169). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Carcinomas
                Hepatocellular Carcinoma
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Gastrointestinal Tumors
                Hepatocellular Carcinoma
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Hepatocellular Carcinoma
                Biology and Life Sciences
                Genetics
                Heredity
                Genetic Mapping
                Variant Genotypes
                Biology and Life Sciences
                Evolutionary Biology
                Population Genetics
                Haplotypes
                Biology and Life Sciences
                Genetics
                Population Genetics
                Haplotypes
                Biology and Life Sciences
                Population Biology
                Population Genetics
                Haplotypes
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Mitosis
                Biology and Life Sciences
                Cell Biology
                Chromosome Biology
                Mitosis
                People and Places
                Geographical Locations
                Asia
                China
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Artificial Gene Amplification and Extension
                Polymerase Chain Reaction
                Research and Analysis Methods
                Molecular Biology Techniques
                Artificial Gene Amplification and Extension
                Polymerase Chain Reaction
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Confidence Intervals
                Medicine and Health Sciences
                Clinical Genetics
                Chromosomal Disorders
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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