Regulation of zygotic genome activation and DNA damage checkpoint acquisition at the mid-blastula transition

Cell Cycle. 2014;13(24):3828-38. doi: 10.4161/15384101.2014.967066.


Following fertilization, oviparous embryos undergo rapid, mostly transcriptionally silent cleavage divisions until the mid-blastula transition (MBT), when large-scale developmental changes occur, including zygotic genome activation (ZGA) and cell cycle remodeling, via lengthening and checkpoint acquisition. Despite their concomitant appearance, whether these changes are co-regulated is unclear. Three models have been proposed to account for the timing of (ZGA). One model implicates a threshold nuclear to cytoplasmic (N:C) ratio, another stresses the importance cell cycle elongation, while the third model invokes a timer mechanism. We show that precocious Chk1 activity in pre-MBT zebrafish embryos elongates cleavage cycles, thereby slowing the increase in the N:C ratio. We find that cell cycle elongation does not lead to transcriptional activation. Rather, ZGA slows in parallel with the N:C ratio. We show further that the DNA damage checkpoint program is maternally supplied and independent of ZGA. Although pre-MBT embryos detect damage and activate Chk2 after induction of DNA double-strand breaks, the Chk1 arm of the DNA damage response is not activated, and the checkpoint is nonfunctional. Our results are consistent with the N:C ratio model for ZGA. Moreover, the ability of precocious Chk1 activity to delay pre-MBT cell cycles indicate that lack of Chk1 activity limits checkpoint function during cleavage cycles. We propose that Chk1 gain-of-function at the MBT underlies cell cycle remodeling, whereas ZGA is regulated independently by the N:C ratio.

Keywords: MBT, Mid-blastula Transition; ZGA, Zygotic genome activation; cell cycle checkpoints; embryogenesis; mid-blastula transition; zygotic genome activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blastula / metabolism*
  • Blastula / radiation effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / radiation effects
  • Checkpoint Kinase 1
  • Checkpoint Kinase 2 / genetics
  • Checkpoint Kinase 2 / metabolism
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Breaks, Double-Stranded / radiation effects
  • DNA Repair
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / metabolism
  • Gamma Rays
  • Genome*
  • Histones / metabolism
  • Hydroxyurea / toxicity
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / genetics
  • Signal Transduction
  • Zebrafish
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism


  • Histones
  • Recombinant Fusion Proteins
  • Zebrafish Proteins
  • Protein Kinases
  • Checkpoint Kinase 2
  • Checkpoint Kinase 1
  • Hydroxyurea