Geminin is required for zygotic gene expression at the Xenopus mid-blastula transition. PLoS One 2012;7(5):e38009
Date
06/05/2012Pubmed ID
22662261Pubmed Central ID
PMC3360639DOI
10.1371/journal.pone.0038009Scopus ID
2-s2.0-84861471202 (requires institutional sign-in at Scopus site) 14 CitationsAbstract
In many organisms early development is under control of the maternal genome and zygotic gene expression is delayed until the mid-blastula transition (MBT). As zygotic transcription initiates, cell cycle checkpoints become activated and the tempo of cell division slows. The mechanisms that activate zygotic transcription at the MBT are incompletely understood, but they are of interest because they may resemble mechanisms that cause stem cells to stop dividing and terminally differentiate. The unstable regulatory protein Geminin is thought to coordinate cell division with cell differentiation. Geminin is a bi-functional protein. It prevents a second round of DNA replication during S and G2 phase by binding and inhibiting the essential replication factor Cdt1. Geminin also binds and inhibits a number of transcription factors and chromatin remodeling proteins and is thought to keep dividing cells in an undifferentiated state. We previously found that the cells of Geminin-deficient Xenopus embryos arrest in G2 phase just after the MBT then disintegrate at the onset of gastrulation. Here we report that they also fail to express most zygotic genes. The gene expression defect is cell-autonomous and is reproduced by over-expressing Cdt1 or by incubating the embryos in hydroxyurea. Geminin deficient and hydroxyurea-treated blastomeres accumulate DNA damage in the form of double stranded breaks. Bypassing the Chk1 pathway overcomes the cell cycle arrest caused by Geminin depletion but does not restore zygotic gene expression. In fact, bypassing the Chk1 pathway by itself induces double stranded breaks and abolishes zygotic transcription. We did not find evidence that Geminin has a replication-independent effect on transcription. We conclude that Geminin is required to maintain genome integrity during the rapid cleavage divisions, and that DNA damage disrupts zygotic gene transcription at the MBT, probably through activation of DNA damage checkpoint pathways.
Author List
Kerns SL, Schultz KM, Barry KA, Thorne TM, McGarry TJAuthor
Sarah L. Kerns PhD Associate Professor in the Radiation Oncology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBlastula
Cell Cycle Checkpoints
Cell Cycle Proteins
DNA Damage
DNA-Binding Proteins
Female
Geminin
Gene Deletion
Gene Expression Regulation, Developmental
Hydroxyurea
Male
Mutation
Protein Binding
T-Box Domain Proteins
Transcription, Genetic
Xenopus
Xenopus Proteins
Zygote
