Alteration of DNA Damage Response Causes Cleft Palate

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.

Diabetes, Oxidative Stress, and DNA Damage Modulate Cranial Neural Crest Cell Development and the Phenotype Variability of Craniofacial Disorders

“…NCC-derived osteogenic progenitors exhibited increased levels of γ-H2AX and p53 activation, which subsequently led to their apoptosis, resulting in cranioskeletal hypoplasia. Interestingly, the loss of Brca1 did not affect osteogenic differentiation, indicating that Brca1-mediated DNA damage repair is critically required for osteoprogenitor survival during craniofacial development ( Kitami et al, 2018 ; Yamaguchi et al, 2021 ).…”

“…Perturbation of any one of these phases of NCC development can lead to variable craniofacial malformations. A growing body of evidence suggests that NCC are particularly sensitive to exogenous environmental stressors such as diabetes, oxidative stress, and DNA damage ( Sakai and Trainor, 2016 ; Sakai et al, 2016 ; Kitami et al, 2018 ; Yamaguchi et al, 2021 ). We postulate that the interactions between these exogenous stressors and genetic risk factors for individual craniofacial malformations compromise NCC viability, thus contributing to the phenotypic variation observed in many craniofacial syndromes.…”

“…Consistent with this idea, DNA damage and genome instability are associated with an increased incidence of cleft lip and/or palate ( Kobayashi et al, 2013 ). Furthermore, mutations in DNA damage repair genes can result in craniofacial malformations, highlighting the importance of maintaining genome stability during normal craniofacial morphogenesis ( Wong et al, 2003 ; Seeman et al, 2004 ; Altmann and Gennery, 2016 ; Sakai et al, 2016 ; Kitami et al, 2018 ; Boone et al, 2019 ; Yamaguchi et al, 2021 ). This led us to postulate that exogenous stressors, particularly oxidative stress and DNA damage, can worsen the damage caused by a particular neural crest cell disruptive mutation, thus exacerbating its phenotypic outcome.…”

Involvement of <i>microRNA-4680-3p</i> against phenytoin-induced cell proliferation inhibition in human palate cells

“…Environmental factors such as medication usage, cigarette smoking, and alcohol consumption are well-known risk factors for CP since they lead to suppression of the expression of specific genes or signaling pathways (Dhulipala et al, 2006;Romitti et al, 1999). Although novel gene mutations associated with CP have been reported (Yamaguchi et al, 2021), it remains unclear how environmental and genetic factors affect CP.…”