Adverse Effects of Nucleotide Excision Repair and Transcription Gene Abnormalities on Human Fetal and Placental Development

Anil Kumar, University at Albany, State University of New York (SUNY)
Amiran Dzutsev, National Cancer Institute, NIH
Roxana Moslehi, University at Albany, State University of New York (SUNY)

Our recent genetic epidemiologic investigation of gestational outcomes associated with abnormalities in trichothiodystrophy nucleotide excision repair (NER) and transcription genes, namely XPD(ERCC2), XPB(ERCC3), TTD-A(GFT2H5), and TTDN1(C7ORF11), revealed significantly increased risk of several severe gestational complications including preeclampsia in affected pregnancies where the fetus had two mutations, but not in unaffected pregnancies where the fetus was either heterozygote or had no mutations. To test our hypothesis that DNA repair/transcription genes are involved in normal placental development and decipher biologic mechanisms, we analyzed gene expression arrays of normal human placentas and placentas from pregnancies complicated with preeclampsia. We found high expression of NER/transcription genes during 14-40 weeks gestation. Comparison of gene signatures implicated dysfunction of DNA-dependent regulation of transcription and response to oxidative stress pathways in pre-eclampsia. Our results indicate an important role for TTD NER/transcription gene products during normal placental development and provide clues as to the etiology of observed complications.