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PloS one
2013;8 (6): e65677.

Susceptibility to DNA damage as a molecular mechanism for non-syndromic cleft lip and palate.

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
Author Information
  1. Gerson Shigeru Kobayashi: Human Genome Research Center, Institute for Biosciences, University of São Paulo, São Paulo, Brazil.
PMID: 23776525 DOI: 10.1371/journal.pone.0065677

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.

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Grants

  1. BB/G021074/1/Biotechnology and Biological Sciences Research Council

MeSH Term

BRCA1 Protein
Cell Cycle
Cells, Cultured
Child
Cleft Lip
Cleft Palate
DNA Breaks, Double-Stranded
DNA Primers
DNA Repair
Dental Pulp
E2F1 Transcription Factor
Flow Cytometry
Gene Expression Profiling
Gene Regulatory Networks
Humans
In Situ Hybridization
MutS Homolog 2 Protein
Protein Array Analysis
Rad51 Recombinase
Real-Time Polymerase Chain Reaction
Stem Cells

Chemicals

BRCA1 Protein
BRCA1 protein, human
DNA Primers
E2F1 Transcription Factor
E2F1 protein, human
RAD51 protein, human
Rad51 Recombinase
MSH2 protein, human
MutS Homolog 2 Protein
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 1

Word Cloud

Created with Highcharts 10.0.0NSCL/PDNAmaycleftmalformationembryonicfindingsaetiologicaloverlapcancercellsco-expressednetworkdouble-strandcellularshowmolecularlippalatedamagemechanismNon-syndromiclip/palatecomplexfrequentcongenitaldeterminedinterplaygeneticenvironmentalfactorsdevelopmentPreviousappointedalterationssimilarbiologicalpathwaysunderpinconditionsusingcombinationtranscriptomicprofilingfunctionalapproachesreportdentalpulpstemexhibitdysregulationgenemainlyassociatedbreakrepaircellcyclecontrolp = 288×10-2-502×10-9includedimportantgenesprocessesBRCA1RAD51MSH2predictedregulatedtranscriptionfactorE2F1FunctionalassayssupportrevealingaccumulatebreaksuponexposureH2O2FurthermoreE2f1Brca1Rad51developingorofacialprimordiaacthubplayingrolemorphogenesisconclusionfirsttimedefencestakepartdeterminingsusceptibilityresultsaccordancehypothesissuggestnewpathogenicdiseaseSusceptibilitynon-syndromic

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