Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties
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{"title"=>"Mitochondrial DNA polymerase POLG1 disease mutations and germline variants promote tumorigenic properties", "type"=>"journal", "authors"=>[{"first_name"=>"Bhupendra", "last_name"=>"Singh", "scopus_author_id"=>"56418939700"}, {"first_name"=>"Kjerstin M.", "last_name"=>"Owens", "scopus_author_id"=>"35071712300"}, {"first_name"=>"Prachi", "last_name"=>"Bajpai", "scopus_author_id"=>"56988835700"}, {"first_name"=>"Mohamed Mokhtar", "last_name"=>"Desouki", "scopus_author_id"=>"6507653387"}, {"first_name"=>"Vinodh", "last_name"=>"Srinivasasainagendra", "scopus_author_id"=>"8927742300"}, {"first_name"=>"Hemant K.", "last_name"=>"Tiwari", "scopus_author_id"=>"7003376624"}, {"first_name"=>"Keshav K.", "last_name"=>"Singh", "scopus_author_id"=>"7404762555"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84949036124", "doi"=>"10.1371/journal.pone.0139846", "pui"=>"607111664", "pmid"=>"26468652", "scopus"=>"2-s2.0-84949036124", "issn"=>"19326203", "isbn"=>"10.1371/journal.pone.0139846"}, "id"=>"0bc06653-5bec-3f91-b6e3-b8c282268031", "abstract"=>"Germline mutations in mitochondrial DNA polymerase gamma (POLG1) induce mitochondrial DNA (mtDNA) mutations, depletion, and decrease oxidative phosphorylation. Earlier, we identified somatic mutations in POLG1 and the contribution of these mutations in human cancer. However, a role for germline variations in POLG1 in human cancers is unknown. In this study, we examined a role for disease associated germline variants of POLG1, POLG1 gene expression, copy number variation and regulation in human cancers. We analyzed the mutations, expression and copy number variation in POLG1 in several cancer databases and validated the analyses in primary breast tumors and breast cancer cell lines. We discovered 5-aza-2'-deoxycytidine led epigenetic regulation of POLG1, mtDNA-encoded genes and increased mitochondrial respiration. We conducted comprehensive race based bioinformatics analyses of POLG1 gene in more than 33,000 European-Americans and 5,000 African-Americans. We identified a mitochondrial disease causing missense variation in polymerase domain of POLG1 protein at amino acid 1143 (E1143G) to be 25 times more prevalent in European-Americans (allele frequency 0.03777) when compared to African-American (allele frequency 0.00151) population. We identified T251I and P587L missense variations in exonuclease and linker region of POLG1 also to be more prevalent in European-Americans. Expression of these variants increased glucose consumption, decreased ATP production and increased matrigel invasion. Interestingly, conditional expression of these variants revealed that matrigel invasion properties conferred by these germline variants were reversible suggesting a role of epigenetic regulators. Indeed, we identified a set of miRNA whose expression was reversible after variant expression was turned off. Together, our studies demonstrate altered genetic and epigenetic regulation of POLG1 in human cancers and suggest a role for POLG1 germline variants in promoting tumorigenic properties.", "link"=>"http://www.mendeley.com/research/mitochondrial-dna-polymerase-polg1-disease-mutations-germline-variants-promote-tumorigenic-propertie", "reader_count"=>24, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>2, "Librarian"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>2, "Student > Bachelor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>2, "Librarian"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>2, "Student > Bachelor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Biochemistry, Genetics and Molecular Biology"=>8, "Agricultural and Biological Sciences"=>5, "Medicine and Dentistry"=>1, "Business, Management and Accounting"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>1, "Social Sciences"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Social Sciences"=>{"Social Sciences"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>5}, "Computer Science"=>{"Computer Science"=>1}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}, "Unspecified"=>{"Unspecified"=>4}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2361071"], "description"=>"<p><b>A.</b> RT PCR analysis of <i>POLG1</i> gene expression in human breast cell lines and Rho<sup>0</sup> cells. <b>B.</b> RT PCR analysis of <i>POLG1</i> gene expression in MDA-MB-231 (MDA-231) cells after 96h of treatment with different doses of 5-aza. Treatment of MDA-231 cells with 5-aza increases expression of <i>POLG1</i> in dose-dependent fashion. <b>C.</b> Expression of mitochondrial genome-encoded genes after 5-aza treatment (1μM, 96h) of MDA-231 cells. <b>D.</b> Increased mitochondrial respiration of MDA-231 cells after 5-aza treatment (1μM) for 96h. <b>E & F.</b> Growth rate (<b>E</b>) and matrigel invasion capacity (<b>F</b>) of MDA-231 cells after treatment with 5-aza (1μM, 96h).</p>", "links"=>[], "tags"=>["mitochondrial DNA polymerase gamma", "decrease oxidative phosphorylation", "POLG 1 germline variants", "1143G", "Mitochondrial DNA Polymerase POLG 1 Disease Mutations", "Copy number variation", "atp", "POLG 1 gene", "expression", "251I", "Germline Variants Promote Tumorigenic Properties Germline mutations", "breast cancer cell lines", "P 587L missense variations", "germline variants", "POLG 1", "matrigel invasion properties", "POLG 1 protein"], "article_id"=>1576629, "categories"=>["Uncategorised"], "users"=>["Bhupendra Singh", "Kjerstin M. Owens", "Prachi Bajpai", "Mohamed Mokhtar Desouki", "Vinodh Srinivasasainagendra", "Hemant K. Tiwari", "Keshav K. Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139846.g005", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_POLG1_is_epigenetically_regulated_/1576629", "title"=>"<i>POLG1</i> is epigenetically regulated.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-15 02:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/2361070"], "description"=>"<p><b>A.</b> Mitochondria-specific functionality of disease causing human POLG1 germline variants E1143G, T251I and P587L as well as double mutants (T251I/P587L) was analyzed using yeast petite formation assay. Individual expression as well as expression of double mutants in yeast increase petite mutants formation. <b>B.</b> Cellular ATP levels in POLG1 E1143G stable cells treated with 1000 ng/ml dox for 10 days. <b>C.</b> Glucose consumption in POLG E1143G stable cells treated with 1000 ng/ml dox for 10 days. <b>D & E.</b> Functionality of a site directed mutation (D1135A) in the conserved region of the polymerase domain of human POLG1 was analyzed. ATP levels (<b>D</b>) and glucose consumption (<b>E</b>) in POLG1 D1135A stable cells treated with 1000 ng/ml dox for 10 days. Bars represent the mean ± s.d. *<i>P</i> < 0.05; Student's t-test.</p>", "links"=>[], "tags"=>["mitochondrial DNA polymerase gamma", "decrease oxidative phosphorylation", "POLG 1 germline variants", "1143G", "Mitochondrial DNA Polymerase POLG 1 Disease Mutations", "Copy number variation", "atp", "POLG 1 gene", "expression", "251I", "Germline Variants Promote Tumorigenic Properties Germline mutations", "breast cancer cell lines", "P 587L missense variations", "germline variants", "POLG 1", "matrigel invasion properties", "POLG 1 protein"], "article_id"=>1576628, "categories"=>["Uncategorised"], "users"=>["Bhupendra Singh", "Kjerstin M. Owens", "Prachi Bajpai", "Mohamed Mokhtar Desouki", "Vinodh Srinivasasainagendra", "Hemant K. Tiwari", "Keshav K. Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139846.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_analyses_of_POLG1_variants_and_mutations_/1576628", "title"=>"Functional analyses of <i>POLG1</i> variants and mutations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-15 02:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/2361067"], "description"=>"<p>Oncomine database analysis of POLG1 upregulation (A) and downregulation (B) in normal (N) versus tumor (T) human tissues. <b>A.</b> Increased POLG1 expression in salivary gland, myeloma, pancreas, kidney, skin, prostate and colorectal cancer. <b>B.</b> Decreased POLG1 expression in lung, head & neck, brain, bladder, cervix, leukemia and esophageal cancer. <b>C.</b> Oncomine database analysis of POLG1 expression in human breast cancer. POLG1 expression is significantly increased in both invasive and ductal breast carcinoma compared to normal breast tissues. <b>D.</b> Immunohistochemical (IHC) analysis of POLG1 expression in benign breast tissue, breast carcinoma and metastatic carcinomas in regional lymph nodes on tissue array containing 53 breast tissue cores with an anti-POLG1 antibody. <b>I & II.</b> Benign liver tissue incubated with (<b>II</b>) and without (<b>I</b>) POLG1 antibody serving as positive and negative control, respectively. <b>III & IV.</b> Representative non-neoplastic breast tissue from patients without and with breast carcinomas, respectively. <b>V & VI.</b> Representative low and high grade ductal carcinoma in situ (DCIS), respectively. Notice high expression of POLG1 in DCIS (arrow) compared to low level of expression in non-neoplastic ducts (arrow head). <b>VII & VIII.</b> Representative low and high grade invasive duct carcinoma (IDC) cases, respectively. <b>IX.</b> Representative invasive lobular carcinoma (ILC) case. <b>X.</b> Representative metastatic breast carcinoma in regional lymph node (LN met). Notice high expression of POLG1 in metastatic tumor (arrow) compared to low level of expression in lymhocytes (arrow head). POLG1 protein was visualized using DAB with hematoxylin counterstain. <b>E.</b> Graph representing the percentage of different immunohistochemistry score of immunoreactivity for POLG1 expression in benign breast tissue, DCIS, IDC, ILC, and LN met. IHC analysis was done on tissue array containing 53 breast tissue cores with anti-POLG1 antibody. Note high expression (score +++) of POLG1 protein in DCIS, IDC, ILC, and LN met compared to benign breast tissues. <b>F.</b> Representative gel pictures from RT PCR study of <i>POLG1</i> mRNA expression in a different set of control breast and breast tumor samples. Decreased expression of <i>POLG1</i> mRNA in two breast tumors and increased in other two breast tumors compared to normal breast tissues are represented here.</p>", "links"=>[], "tags"=>["mitochondrial DNA polymerase gamma", "decrease oxidative phosphorylation", "POLG 1 germline variants", "1143G", "Mitochondrial DNA Polymerase POLG 1 Disease Mutations", "Copy number variation", "atp", "POLG 1 gene", "expression", "251I", "Germline Variants Promote Tumorigenic Properties Germline mutations", "breast cancer cell lines", "P 587L missense variations", "germline variants", "POLG 1", "matrigel invasion properties", "POLG 1 protein"], "article_id"=>1576625, "categories"=>["Uncategorised"], "users"=>["Bhupendra Singh", "Kjerstin M. Owens", "Prachi Bajpai", "Mohamed Mokhtar Desouki", "Vinodh Srinivasasainagendra", "Hemant K. Tiwari", "Keshav K. Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139846.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_POLG1_expression_in_primary_breast_tumors_/1576625", "title"=>"POLG1 expression in primary breast tumors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-15 02:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/2361073"], "description"=>"<p><sup>a</sup>Semi-quantitative scoring of immunoreactivity where</p><p>+, < 10% positive cells;</p><p>++, 10–50% positive cells;</p><p>+++, > 50% positive cells</p><p>POLG1 immunohistochemistry in benign breast ductal epithelium (n = 13) and neoplastic breast tissue (n = 40).</p>", "links"=>[], "tags"=>["mitochondrial DNA polymerase gamma", "decrease oxidative phosphorylation", "POLG 1 germline variants", "1143G", "Mitochondrial DNA Polymerase POLG 1 Disease Mutations", "Copy number variation", "atp", "POLG 1 gene", "expression", "251I", "Germline Variants Promote Tumorigenic Properties Germline mutations", "breast cancer cell lines", "P 587L missense variations", "germline variants", "POLG 1", "matrigel invasion properties", "POLG 1 protein"], "article_id"=>1576631, "categories"=>["Uncategorised"], "users"=>["Bhupendra Singh", "Kjerstin M. Owens", "Prachi Bajpai", "Mohamed Mokhtar Desouki", "Vinodh Srinivasasainagendra", "Hemant K. Tiwari", "Keshav K. Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139846.t001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_POLG1_immunohistochemistry_in_benign_breast_ductal_epithelium_n_13_and_neoplastic_breast_tissue_n_40_/1576631", "title"=>"POLG1 immunohistochemistry in benign breast ductal epithelium (n = 13) and neoplastic breast tissue (n = 40).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-10-15 02:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/2361074"], "description"=>"<div><p>Germline mutations in mitochondrial DNA polymerase gamma (POLG1) induce mitochondrial DNA (mtDNA) mutations, depletion, and decrease oxidative phosphorylation. Earlier, we identified somatic mutations in POLG1 and the contribution of these mutations in human cancer. However, a role for germline variations in POLG1 in human cancers is unknown. In this study, we examined a role for disease associated germline variants of POLG1, POLG1 gene expression, copy number variation and regulation in human cancers. We analyzed the mutations, expression and copy number variation in <i>POLG1</i> in several cancer databases and validated the analyses in primary breast tumors and breast cancer cell lines. We discovered 5-aza-2'-deoxycytidine led epigenetic regulation of <i>POLG1</i>, mtDNA-encoded genes and increased mitochondrial respiration. We conducted comprehensive race based bioinformatics analyses of <i>POLG1</i> gene in more than 33,000 European-Americans and 5,000 African-Americans. We identified a mitochondrial disease causing missense variation in polymerase domain of POLG1 protein at amino acid 1143 (E1143G) to be 25 times more prevalent in European-Americans (allele frequency 0.03777) when compared to African-American (allele frequency 0.00151) population. We identified T251I and P587L missense variations in exonuclease and linker region of POLG1 also to be more prevalent in European-Americans. Expression of these variants increased glucose consumption, decreased ATP production and increased matrigel invasion. Interestingly, conditional expression of these variants revealed that matrigel invasion properties conferred by these germline variants were reversible suggesting a role of epigenetic regulators. Indeed, we identified a set of miRNA whose expression was reversible after variant expression was turned off. Together, our studies demonstrate altered genetic and epigenetic regulation of POLG1 in human cancers and suggest a role for POLG1 germline variants in promoting tumorigenic properties.</p></div>", "links"=>[], "tags"=>["mitochondrial DNA polymerase gamma", "decrease oxidative phosphorylation", "POLG 1 germline variants", "1143G", "Mitochondrial DNA Polymerase POLG 1 Disease Mutations", "Copy number variation", "atp", "POLG 1 gene", "expression", "251I", "Germline Variants Promote Tumorigenic Properties Germline mutations", "breast cancer cell lines", "P 587L missense variations", "germline variants", "POLG 1", "matrigel invasion properties", "POLG 1 protein"], "article_id"=>1576632, "categories"=>["Uncategorised"], "users"=>["Bhupendra Singh", "Kjerstin M. Owens", "Prachi Bajpai", "Mohamed Mokhtar Desouki", "Vinodh Srinivasasainagendra", "Hemant K. Tiwari", "Keshav K. Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139846", "stats"=>{"downloads"=>2, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mitochondrial_DNA_Polymerase_POLG1_Disease_Mutations_and_Germline_Variants_Promote_Tumorigenic_Properties_/1576632", "title"=>"Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-15 02:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/2361072"], "description"=>"<p>Functional reversibility of POLG1 variants (E1143G, T251I, P587L, T251I/P587L) and mutation (D1135A) was analyzed by performing matrigel invasion assay with MCF-7 Tet-on cells expressing these variants/mutations of POLG1. Cell were treated with 1000 ng/ml dox and sorted for GFP fluorescence. Cells were grown in the presence of dox for 5 days, then the media was changed to dox-free media for 7 additional days. <b>A-E.</b> Increased matrigel invasion capacity of POLG1 variants E1143G (<b>A</b>), T251I (<b>B</b>), P587L (<b>C</b>), T251I/P587L (<b>D</b>) or mutation D1135A (<b>E</b>) after 5 days of dox treatment and reversal of invasion capacity after growing the cells in dox-free media for 7 additional days (day 12). Data represents fold change of invading cells normalized to day 0 ± s.d. *<i>P</i> < 0.05; Student's t-test. <b>F.</b> mtDNA content in MCF-7 tet-on cells transfected with POLG1 D1135A after 5 days of dox treatment and in these cells after 7 more days of culturing in the absence of dox (<b>i</b>). Illumina human miRNA expression array results from POLG1 D1135A expressing cells after 5 days of dox treatment are represented as a scatter plot (Day 5) (<b>ii</b>). POLG1 D1135A cells were then grown in the absence of dox for 7 more days and miRNA expression array results from these cells are also presented as a scatter plot (Day 12) (<b>iii</b>).</p>", "links"=>[], "tags"=>["mitochondrial DNA polymerase gamma", "decrease oxidative phosphorylation", "POLG 1 germline variants", "1143G", "Mitochondrial DNA Polymerase POLG 1 Disease Mutations", "Copy number variation", "atp", "POLG 1 gene", "expression", "251I", "Germline Variants Promote Tumorigenic Properties Germline mutations", "breast cancer cell lines", "P 587L missense variations", "germline variants", "POLG 1", "matrigel invasion properties", "POLG 1 protein"], "article_id"=>1576630, "categories"=>["Uncategorised"], "users"=>["Bhupendra Singh", "Kjerstin M. Owens", "Prachi Bajpai", "Mohamed Mokhtar Desouki", "Vinodh Srinivasasainagendra", "Hemant K. Tiwari", "Keshav K. Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139846.g006", "stats"=>{"downloads"=>3, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_reversibility_of_POLG1_variants_and_mutations_/1576630", "title"=>"Functional reversibility of <i>POLG1</i> variants and mutations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-15 02:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/2361069"], "description"=>"<p><b>A.</b> Distribution of different types of variations such as mutations, deletions and amplifications in <i>POLG1</i> gene in different human cancers were analyzed using cBioPortal database and represented here as a bar graph. <b>B.</b> All the reported somatic mutations in human POLG1 in different human tumors were analyzed from Cosmic database as well as from published studies [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139846#pone.0139846.ref021\" target=\"_blank\">21</a>,<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139846#pone.0139846.ref022\" target=\"_blank\">22</a>] and a schematic showing location of these tumor somatic mutations in human POLG1 protein is presented here. <b>C.</b> Distribution pattern of different types of somatic mutations in POLG1 in human cancers was analyzed using Cosmic database and is presented here as a pie chart.</p>", "links"=>[], "tags"=>["mitochondrial DNA polymerase gamma", "decrease oxidative phosphorylation", "POLG 1 germline variants", "1143G", "Mitochondrial DNA Polymerase POLG 1 Disease Mutations", "Copy number variation", "atp", "POLG 1 gene", "expression", "251I", "Germline Variants Promote Tumorigenic Properties Germline mutations", "breast cancer cell lines", "P 587L missense variations", "germline variants", "POLG 1", "matrigel invasion properties", "POLG 1 protein"], "article_id"=>1576627, "categories"=>["Uncategorised"], "users"=>["Bhupendra Singh", "Kjerstin M. Owens", "Prachi Bajpai", "Mohamed Mokhtar Desouki", "Vinodh Srinivasasainagendra", "Hemant K. Tiwari", "Keshav K. Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139846.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_POLG1_is_frequently_mutated_in_primary_tumors_/1576627", "title"=>"<i>POLG1</i> is frequently mutated in primary tumors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-15 02:52:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/2361068"], "description"=>"<p><b>A.</b> Human cancer data from Cosmic database was analyzed for CNVs in <i>POLG1</i> gene on February 19, 2014. Gain or loss of <i>POLG1</i> copy numbers in different human cancers are represented as % variation. <b>B & C.</b> Spectral Karyotyping results from MDA-MB-231 (<b>B</b>) and BT-549 (<b>C</b>) are represented. In MDA-MB-231 cells, a chromosome translocation involving chromosome 15 is observed, while in BT-459 cells line two normal chromosome 15 and an extra copy of the <i>POLG1</i> gene is identified.</p>", "links"=>[], "tags"=>["mitochondrial DNA polymerase gamma", "decrease oxidative phosphorylation", "POLG 1 germline variants", "1143G", "Mitochondrial DNA Polymerase POLG 1 Disease Mutations", "Copy number variation", "atp", "POLG 1 gene", "expression", "251I", "Germline Variants Promote Tumorigenic Properties Germline mutations", "breast cancer cell lines", "P 587L missense variations", "germline variants", "POLG 1", "matrigel invasion properties", "POLG 1 protein"], "article_id"=>1576626, "categories"=>["Uncategorised"], "users"=>["Bhupendra Singh", "Kjerstin M. Owens", "Prachi Bajpai", "Mohamed Mokhtar Desouki", "Vinodh Srinivasasainagendra", "Hemant K. Tiwari", "Keshav K. Singh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139846.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Frequent_POLG1_copy_number_variations_in_primary_tumors_and_in_cancer_cell_lines_/1576626", "title"=>"Frequent <i>POLG1</i> copy number variations in primary tumors and in cancer cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-15 02:52:41"}

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{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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