Abstract
Cleft palate is one of the most common craniofacial birth defects, however, little is known about how changes in the DNA damage response (DDR) cause cleft palate. To determine the role of DDR during palatogenesis, the DDR process was altered using a pharmacological intervention approach. A compromised DDR caused by a poly (ADP-ribose) polymerase (PARP) enzyme inhibitor resulted in cleft palate in wild-type mouse embryos, with increased DNA damage and apoptosis. In addition, a mouse genetic approach was employed to disrupt breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2), known as key players in DDR. An ectomesenchymal-specific deletion of Brca1 or Brca2 resulted in cleft palate due to attenuation of cell survival. This was supported by the phenotypes of the ectomesenchymal-specific Brca1/Brca2 double-knockout mice. The cleft palate phenotype was rescued by superimposing p53 null alleles, demonstrating that the BRCA1/2–p53 DDR pathway is critical for palatogenesis. Our study highlights the importance of DDR in palatogenesis.
Highlights
Cleft palate occurs in about one in every 500∼700 live births (Stanier and Moore, 2004; Dixon et al, 2011)
These results indicate that breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) play a critical role during palatogenesis in murine neural crest-derived ectomesenchymal cells, but not in epithelial cells
We found a novel connection between the etiology of cleft palate and the DNA damage response (DDR), mainly via BRCA1/2-p53–dependent mechanisms
Summary
Cleft palate occurs in about one in every 500∼700 live births (Stanier and Moore, 2004; Dixon et al, 2011). Affected individuals still face serious functional and social challenges throughout their lives, with cleft palate imposing tremendous psychological and financial burdens on patients and their families. Tremendous progress has been made toward understanding the genetic control(s) of this craniofacial abnormality (Murray, 2002; Bush and Jiang, 2012; Marazita, 2012). These studies clearly showed that genetic and cellular signaling pathways are tightly linked during palatogenesis, but the molecular details of cleft palate remain elusive. It is critical to uncover novel etiological mechanisms underlying cleft palate, enabling us to prevent and develop potential therapeutic strategies for this malformation
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