Susceptibility to DNA damage as a molecular mechanism for non-syndromic cleft lip and palate.
Susceptibility to DNA damage as a molecular mechanism for non-syndromic cleft lip and palate.
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DOI：
10.1371/journal.pone.0065677
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Passos-Bueno MR
中科院分区：
文献类型：
--
作者：
Kobayashi GS;Alvizi L;Sunaga DY;Francis-West P;Kuta A;Almada BV;Ferreira SG;de Andrade-Lima LC;Bueno DF;Raposo-Amaral CE;Menck CF;Passos-Bueno MR
非综合征性唇腭裂（NSCL/P）是一种复杂的、常见的先天性畸形，由胚胎发育过程中遗传和环境因素的相互作用决定。以前的研究结果已经指定了NSCL/P和癌症之间的病因重叠，并且类似生物学途径的改变可能是这两种情况的基础。在这里，使用转录组学分析和功能方法的组合，我们报告NSCL/P牙髓干细胞表现出主要与DNA双链断裂修复和细胞周期控制相关的共表达基因网络的失调（p = 2.88×10−2-5.02×10−9）。 该网络包括这些细胞过程的重要基因，如BRCA 1，RAD 51和MSH 2，预计这些基因受转录因子E2 F1调控。功能测定支持这些发现，揭示了NSCL/P细胞在暴露于H2 O2时积累DNA双链断裂。此外，我们表明，E2 f1，Brca 1和Rad 51共表达在发展中的胚胎orofacial原基，并可能作为一个分子枢纽发挥作用的唇和腭形态发生。总之，我们首次表明，细胞对DNA损伤的防御可能参与确定非小细胞淋巴细胞白血病/P的易感性。这些结果与这种畸形和癌症之间的病因重叠的假设是一致的，并提出了一种新的致病机制的疾病。
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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影响因子：
4.8
作者：
Bueno, Daniela Franco;Sunaga, Daniele Yumi;Kobayashi, Gerson Shigeru;Aguena, Meire;Raposo-Amaral, Cassio Eduardo;Masotti, Cibele;Cruz, Lucas Alvizi;Pearson, Peter Lees;Passos-Bueno, Maria Rita
通讯作者：
Passos-Bueno, Maria Rita
影响因子：
3.1
作者：
Alsdorf, Rachel;Wyszynski, Diego F
通讯作者：
Wyszynski, Diego F
影响因子：
0.9
作者：
Costa, Andre de Mendona;Bueno, Daniela F.;Passos-Bueno, Maria Rita
通讯作者：
Passos-Bueno, Maria Rita
影响因子：
14.5
作者：
Dixon, K;Kopras, E
通讯作者：
Kopras, E
影响因子：
30.8
作者：
Birnbaum, Stefanie;Ludwig, Kerstin U.;Mangold, Elisabeth
通讯作者：
Mangold, Elisabeth