Current Biology
Volume 31, Issue 12, 21 June 2021, Pages 2633-2642.e6
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Excess histone H3 is a competitive Chk1 inhibitor that controls cell-cycle remodeling in the early Drosophila embryo

https://doi.org/10.1016/j.cub.2021.03.035Get rights and content
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Highlights

  • Histone H3 controls the embryonic cell cycle independent of chromatin incorporation

  • Excess H3-tail reduces activity of the checkpoint kinase Chk1

  • Hyper-abundant H3 in the embryo acts as a direct competitive Chk1 inhibitor

  • Mathematical modeling recapitulates the H3 regulation of cell-cycle slowing

Summary

The DNA damage checkpoint is crucial to protect genome integrity.1,2 However, the early embryos of many metazoans sacrifice this safeguard to allow for rapid cleavage divisions that are required for speedy development. At the mid-blastula transition (MBT), embryos switch from rapid cleavage divisions to slower, patterned divisions with the addition of gap phases and acquisition of DNA damage checkpoints. The timing of the MBT is dependent on the nuclear-to-cytoplasmic (N/C ratio)3, 4, 5, 6, 7 and the activation of the checkpoint kinase, Chk1.8, 9, 10, 11, 12, 13, 14, 15, 16, 17 How Chk1 activity is coupled to the N/C ratio has remained poorly understood. Here, we show that dynamic changes in histone H3 availability in response to the increasing N/C ratio control Chk1 activity and thus time the MBT in the Drosophila embryo. We show that excess H3 in the early cycles interferes with cell-cycle slowing independent of chromatin incorporation. We find that the N-terminal tail of H3 acts as a competitive inhibitor of Chk1 in vitro and reduces Chk1 activity in vivo. Using a H3-tail mutant that has reduced Chk1 inhibitor activity, we show that the amount of available Chk1 sites in the H3 pool controls the dynamics of cell-cycle progression. Mathematical modeling quantitatively supports a mechanism where titration of H3 during early cleavage cycles regulates Chk1-dependent cell-cycle slowing. This study defines Chk1 regulation by H3 as a key mechanism that coordinates cell-cycle remodeling with developmental progression.

Keywords

cell cycle
checkpoint
Chk1
embryo
mid-blastula transition
MBT
nuclear-to-cytoplasmic ratio
N/C ratio
DNA damage
histone
H3-tail
competitive inhibition
Drosophila

Cited by (0)

3

Twitter: @_yuki_shindo

4

Twitter: @AAAmodeo

5

Lead contact