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

TY - JOUR

T1 - Susceptibility to DNA damage as a molecular mechanism for non-syndromic cleft lip and palate

AU - Kobayashi, Gerson Shigeru

AU - Alvizi, Lucas

AU - Sunaga, Daniele Yumi

AU - Francis-West, Philippa

AU - Kuta, Anna

AU - Almada, Bruno Vinícius Pimenta

AU - Ferreira, Simone Gomes

AU - de Andrade-Lima, Leonardo Carmo

AU - Bueno, Daniela Franco

AU - Raposo-Amaral, Cássio Eduardo

AU - Menck, Carlos Frederico

AU - Passos-Bueno, Maria Rita

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pone.0065677

DO - 10.1371/journal.pone.0065677

M3 - Article

C2 - 23776525

SN - 1932-6203

VL - 8

SP - e65677

JO - PLoS ONE

JF - PLoS ONE

IS - 6

ER -