Susceptibility to DNA Damage as a Molecular Mechanism for Non-Syndromic Cleft Lip and Palate
Publication Date
June 12, 2013
Journal
PLOS ONE
Authors
Gerson Shigeru Kobayashi, Lucas Alvizi, Daniele Yumi Sunaga, Philippa Francis West, et al
Volume
8
Issue
6
Pages
e65677
DOI
https://dx.plos.org/10.1371/journal.pone.0065677
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0065677
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/23776525
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680497
Europe PMC
http://europepmc.org/abstract/MED/23776525
Web of Science
000320322400045
Scopus
84878920367
Mendeley
http://www.mendeley.com/research/susceptibility-dna-damage-molecular-mechanism-nonsyndromic-cleft-lip-palate-5
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Mendeley | Further Information

{"title"=>"Susceptibility to DNA Damage as a Molecular Mechanism for Non-Syndromic Cleft Lip and Palate", "type"=>"journal", "authors"=>[{"first_name"=>"Gerson Shigeru", "last_name"=>"Kobayashi", "scopus_author_id"=>"26532952800"}, {"first_name"=>"Lucas", "last_name"=>"Alvizi", "scopus_author_id"=>"55762907100"}, {"first_name"=>"Daniele Yumi", "last_name"=>"Sunaga", "scopus_author_id"=>"24470105800"}, {"first_name"=>"Philippa", "last_name"=>"Francis-West", "scopus_author_id"=>"7003730165"}, {"first_name"=>"Anna", "last_name"=>"Kuta", "scopus_author_id"=>"24399296400"}, {"first_name"=>"Bruno Vinícius Pimenta", "last_name"=>"Almada", "scopus_author_id"=>"42261157200"}, {"first_name"=>"Simone Gomes", "last_name"=>"Ferreira", "scopus_author_id"=>"55762956600"}, {"first_name"=>"Leonardo Carmo", "last_name"=>"de Andrade-Lima", "scopus_author_id"=>"55736058100"}, {"first_name"=>"Daniela Franco", "last_name"=>"Bueno", "scopus_author_id"=>"10339764000"}, {"first_name"=>"Cássio Eduardo", "last_name"=>"Raposo-Amaral", "scopus_author_id"=>"13610095800"}, {"first_name"=>"Carlos Frederico", "last_name"=>"Menck", "scopus_author_id"=>"7004842673"}, {"first_name"=>"Maria Rita", "last_name"=>"Passos-Bueno", "scopus_author_id"=>"56571311900"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84878920367", "issn"=>"19326203", "scopus"=>"2-s2.0-84878920367", "pmid"=>"23776525", "pui"=>"369102492", "isbn"=>"1932-6203", "doi"=>"10.1371/journal.pone.0065677"}, "id"=>"3a3bd48e-41a0-33f1-9b85-85047a5a278e", "abstract"=>"Non-syndromic cleft lip/palate (NSCL/P) is a complex, frequent congenital malformation, determined by the interplay between genetic and environmental factors during embryonic development. Previous findings have appointed an aetiological overlap between NSCL/P and cancer, and alterations in similar biological pathways may underpin both conditions. Here, using a combination of transcriptomic profiling and functional approaches, we report that NSCL/P dental pulp stem cells exhibit dysregulation of a co-expressed gene network mainly associated with DNA double-strand break repair and cell cycle control (p = 2.88×10(-2)-5.02×10(-9)). This network included important genes for these cellular processes, such as BRCA1, RAD51, and MSH2, which are predicted to be regulated by transcription factor E2F1. Functional assays support these findings, revealing that NSCL/P cells accumulate DNA double-strand breaks upon exposure to H2O2. Furthermore, we show that E2f1, Brca1 and Rad51 are co-expressed in the developing embryonic orofacial primordia, and may act as a molecular hub playing a role in lip and palate morphogenesis. In conclusion, we show for the first time that cellular defences against DNA damage may take part in determining the susceptibility to NSCL/P. These results are in accordance with the hypothesis of aetiological overlap between this malformation and cancer, and suggest a new pathogenic mechanism for the disease.", "link"=>"http://www.mendeley.com/research/susceptibility-dna-damage-molecular-mechanism-nonsyndromic-cleft-lip-palate-5", "reader_count"=>24, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Student > Doctoral Student"=>2, "Researcher"=>4, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>4, "Student > Master"=>3, "Student > Bachelor"=>5, "Professor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Student > Doctoral Student"=>2, "Researcher"=>4, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>4, "Student > Master"=>3, "Student > Bachelor"=>5, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Nursing and Health Professions"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>9, "Medicine and Dentistry"=>9, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Computer Science"=>{"Computer Science"=>1}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Colombia"=>1, "United States"=>1, "Brazil"=>1, "Germany"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1084619"], "description"=>"<p>(A) Smaller graph - Comparison of the fraction of γ-H2AX<sup>+</sup>cells between NSCL/P and control cells, at 6 and 24 hours of treatment with H<sub>2</sub>O<sub>2</sub>. Large graph – Individual quantitation of γ-H2AX<sup>+</sup> cells, revealing the subgroups (I–III) within the NSCL/P samples. (*) p<0.05. (B) Representative γ-H2AX and PI profiles depicting DSB and cell cycle distribution, for each NSCL/P subgroup and controls. (C) Quantitation of sub-G1 cells, revealing a significant increment in NSCL/P subgroup II, at 24 hours of treatment, as compared to the other subgroups and the controls. (**) F = 6.04; p<0.005. (D) Relative expression of <i>CDC45L</i> following treatment with H<sub>2</sub>O<sub>2</sub>, revealing a significant decrease in NSCL/P samples at both time points, by comparison to controls. (*) p<0.05.</p>", "links"=>[], "tags"=>["Biochemistry", "Nucleic acids", "dna", "DNA repair", "developmental biology", "morphogenesis", "Birth defects", "stem cells", "genetics", "Molecular genetics", "Gene regulation", "gene expression", "Gene networks", "Genetics of disease", "Human genetics", "cells", "heterogeneous", "patterns", "dsb"], "article_id"=>718072, "categories"=>["Biological Sciences"], "users"=>["Gerson Shigeru Kobayashi", "Lucas Alvizi", "Daniele Yumi Sunaga", "Philippa Francis-West", "Anna Kuta", "Bruno Vinícius Pimenta Almada", "Simone Gomes Ferreira", "Leonardo Carmo de Andrade-Lima", "Daniela Franco Bueno", "Cássio Eduardo Raposo-Amaral", "Carlos Frederico Menck", "Maria Rita Passos-Bueno"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0065677.g003", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NSCL_P_cells_exhibit_a_heterogeneous_response_to_H_2_O_2_with_distinct_patterns_of_DSB_accumulation_/718072", "title"=>"NSCL/P cells exhibit a heterogeneous response to H<sub>2</sub>O<sub>2</sub>, with distinct patterns of DSB accumulation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-12 02:14:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1084622"], "description"=>"<p>Whole-mount <i>in situ</i> hybridisation (A–F) showing the expression of <i>Brca1</i> (A, D), <i>Rad51</i> (B, E) and <i>E2F1</i> (C, F) in E11.5 (A–C) and E12.5 (D–F) embryos. Expression is indicated by the blue/purple staining. A–C are sagittal views of the developing head whilst A’–C’ are frontal sections through the embryos shown in A–C. A’’–C’’ show high power views through the developing maxillary primordia, lateral and medial nasal processes. E–F are frontal sections through the developing E12.5 palatal shelves. <i>e</i>, eye; <i>l</i>, lateral nasal process; <i>m</i>, medial nasal process; <i>Md</i>, mandibular primordia; <i>Mx</i>, maxillary primordia; <i>ps</i>, palatal shelves.</p>", "links"=>[], "tags"=>["Biochemistry", "Nucleic acids", "dna", "DNA repair", "developmental biology", "morphogenesis", "Birth defects", "stem cells", "genetics", "Molecular genetics", "Gene regulation", "gene expression", "Gene networks", "Genetics of disease", "Human genetics", "facial"], "article_id"=>718075, "categories"=>["Biological Sciences"], "users"=>["Gerson Shigeru Kobayashi", "Lucas Alvizi", "Daniele Yumi Sunaga", "Philippa Francis-West", "Anna Kuta", "Bruno Vinícius Pimenta Almada", "Simone Gomes Ferreira", "Leonardo Carmo de Andrade-Lima", "Daniela Franco Bueno", "Cássio Eduardo Raposo-Amaral", "Carlos Frederico Menck", "Maria Rita Passos-Bueno"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0065677.g004", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_Brca1_Rad51_and_E2f1_in_the_developing_facial_primordia_/718075", "title"=>"Expression of <i>Brca1</i>, <i>Rad51</i> and <i>E2f1</i> in the developing facial primordia.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-12 02:14:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1084617"], "description"=>"<p>(A) Supervised similarity cluster based on <i>BRCA1</i> expression (avg. homogeneity = 0.974). Transcription factor binding sites significantly over-represented in the cluster are marked in grey, for each motif identified (Bonferroni-adjusted p-value <0.05). (B) GO attributes enriched in the similarity cluster and their respective representation among the 30 clustered genes, expressed in percentages ([*] Bootstrap-adjusted p-values = 0.001, raw p-values were used in the chart). (C) Analysis of transcription factor-gene interactions. ChIP-chip data from FANTOM4 were used to validate the interaction between E2F1 and 23 out of the 30 genes of the similarity cluster. The thickness of the arrows indicates how often the interaction has been experimentally detected; node colours represent the level of expression in the cell lines used to assemble the database, from low (light) to high (dark).</p>", "links"=>[], "tags"=>["Biochemistry", "Nucleic acids", "dna", "DNA repair", "developmental biology", "morphogenesis", "Birth defects", "stem cells", "genetics", "Molecular genetics", "Gene regulation", "gene expression", "Gene networks", "Genetics of disease", "Human genetics", "patterns", "co-expression", "e2f1"], "article_id"=>718070, "categories"=>["Biological Sciences"], "users"=>["Gerson Shigeru Kobayashi", "Lucas Alvizi", "Daniele Yumi Sunaga", "Philippa Francis-West", "Anna Kuta", "Bruno Vinícius Pimenta Almada", "Simone Gomes Ferreira", "Leonardo Carmo de Andrade-Lima", "Daniela Franco Bueno", "Cássio Eduardo Raposo-Amaral", "Carlos Frederico Menck", "Maria Rita Passos-Bueno"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0065677.g002", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NSCL_P_patterns_of_co_expression_are_associated_with_DNA_repair_and_suggest_E2F1_as_a_regulator_/718070", "title"=>"NSCL/P patterns of co-expression are associated with DNA repair, and suggest E2F1 as a regulator.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-12 02:14:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1084614"], "description"=>"<p>(A) IPA network. DEGs were used to assemble a functional interaction map. Lines with arrowheads represent that one molecule acts on another, while regular lines represent protein interactions. Down-regulated genes are shown as green nodes, whereas genes without differential expression are shown as blank nodes. (B) Top 10 Canonical Pathways significantly enriched among the 228 DEGs (Fisher’s Exact Test, p-value <0.01). (C) ‘Role of BRCA1 in DNA Damage Response’ Canonical Pathway.</p>", "links"=>[], "tags"=>["Biochemistry", "Nucleic acids", "dna", "DNA repair", "developmental biology", "morphogenesis", "Birth defects", "stem cells", "genetics", "Molecular genetics", "Gene regulation", "gene expression", "Gene networks", "Genetics of disease", "Human genetics", "cells", "dysregulation"], "article_id"=>718067, "categories"=>["Biological Sciences"], "users"=>["Gerson Shigeru Kobayashi", "Lucas Alvizi", "Daniele Yumi Sunaga", "Philippa Francis-West", "Anna Kuta", "Bruno Vinícius Pimenta Almada", "Simone Gomes Ferreira", "Leonardo Carmo de Andrade-Lima", "Daniela Franco Bueno", "Cássio Eduardo Raposo-Amaral", "Carlos Frederico Menck", "Maria Rita Passos-Bueno"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0065677.g001", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NSCL_P_cells_exhibit_a_gene_expression_profile_associated_with_dysregulation_of_DNA_repair_and_cell_cycle_control_/718067", "title"=>"NSCL/P cells exhibit a gene expression profile associated with dysregulation of DNA repair and cell cycle control.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-12 02:14:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/1084625", "https://ndownloader.figshare.com/files/1084626", "https://ndownloader.figshare.com/files/1084627", "https://ndownloader.figshare.com/files/1084629", "https://ndownloader.figshare.com/files/1084632", "https://ndownloader.figshare.com/files/1084637", "https://ndownloader.figshare.com/files/1084638", "https://ndownloader.figshare.com/files/1084640", "https://ndownloader.figshare.com/files/1084641"], "description"=>"<div><p>Non-syndromic cleft lip/palate (NSCL/P) is a complex, frequent congenital malformation, determined by the interplay between genetic and environmental factors during embryonic development. Previous findings have appointed an aetiological overlap between NSCL/P and cancer, and alterations in similar biological pathways may underpin both conditions. Here, using a combination of transcriptomic profiling and functional approaches, we report that NSCL/P dental pulp stem cells exhibit dysregulation of a co-expressed gene network mainly associated with DNA double-strand break repair and cell cycle control (p = 2.88×10<sup>−2</sup>–5.02×10<sup>−9</sup>). This network included important genes for these cellular processes, such as <i>BRCA1</i>, <i>RAD51</i>, and <i>MSH2</i>, which are predicted to be regulated by transcription factor E2F1. Functional assays support these findings, revealing that NSCL/P cells accumulate DNA double-strand breaks upon exposure to H<sub>2</sub>O<sub>2</sub>. Furthermore, we show that <i>E2f1</i>, <i>Brca1</i> and <i>Rad51</i> are co-expressed in the developing embryonic orofacial primordia, and may act as a molecular hub playing a role in lip and palate morphogenesis. In conclusion, we show for the first time that cellular defences against DNA damage may take part in determining the susceptibility to NSCL/P. These results are in accordance with the hypothesis of aetiological overlap between this malformation and cancer, and suggest a new pathogenic mechanism for the disease.</p></div>", "links"=>[], "tags"=>["Biochemistry", "Nucleic acids", "dna", "DNA repair", "developmental biology", "morphogenesis", "Birth defects", "stem cells", "genetics", "Molecular genetics", "Gene regulation", "gene expression", "Gene networks", "Genetics of disease", "Human genetics", "molecular", "non-syndromic", "cleft"], "article_id"=>718078, "categories"=>["Biological Sciences"], "users"=>["Gerson Shigeru Kobayashi", "Lucas Alvizi", "Daniele Yumi Sunaga", "Philippa Francis-West", "Anna Kuta", "Bruno Vinícius Pimenta Almada", "Simone Gomes Ferreira", "Leonardo Carmo de Andrade-Lima", "Daniela Franco Bueno", "Cássio Eduardo Raposo-Amaral", "Carlos Frederico Menck", "Maria Rita Passos-Bueno"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0065677.s001", "https://dx.doi.org/10.1371/journal.pone.0065677.s002", "https://dx.doi.org/10.1371/journal.pone.0065677.s003", "https://dx.doi.org/10.1371/journal.pone.0065677.s004", "https://dx.doi.org/10.1371/journal.pone.0065677.s005", "https://dx.doi.org/10.1371/journal.pone.0065677.s006", "https://dx.doi.org/10.1371/journal.pone.0065677.s007", "https://dx.doi.org/10.1371/journal.pone.0065677.s008", "https://dx.doi.org/10.1371/journal.pone.0065677.s009"], "stats"=>{"downloads"=>7, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Susceptibility_to_DNA_Damage_as_a_Molecular_Mechanism_for_Non_Syndromic_Cleft_Lip_and_Palate_/718078", "title"=>"Susceptibility to DNA Damage as a Molecular Mechanism for Non-Syndromic Cleft Lip and Palate", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-06-12 02:14:38"}

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Relative Metric

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