447partial activation of mitotic events. These data suggest that cyclin accumulation
alone is not enough to mediate all aspects of rapid cell cycle progression
(McCleland et al. 2009a).
A second mechanism for maintaining short cell cycles could rely on DNA
replication itself. Replication occupies the majority of interphase during cleavage
divisions and proceeds quickly due to the close proximity of origins of replication
(Harland and Laskey 1980 ; Spradling 1999 ). Inhibiting replication in syncytial
embryos by injecting Geminin, which blocks the licensing of origins (McGarry and
Kirschner 1998 ; Quinn et al. 2001 ), abolished S-phase and led to premature mitotic
entry, demonstrating that replication defines interphase length in cleavage-stage
embryos (McCleland et al. 2009b). This idea was corroborated in Xenopus, where
replication factors were recently identified that can directly modify cleavage cycle
lengths. Highly expressed during the cleavage stages, Cut5, Treslin, Drf5, and
RecQ4 become limiting at the MBT, coinciding with cell cycle elongation.
Importantly, overexpression of these factors abolished cell cycle lengthening at the
MBT (Collart et al. 2013 ).
In conclusion, pre-MBT cells are preloaded with many of the same cell cycle
regulators as seen in most somatic cells. However, it is their specialized regulation
that leads to rapid cell proliferation.
9.2.3 Cell Cycle Checkpoints in Early Embryogenesis
Cell cycle checkpoints are present in almost all nonpathologic somatic cells to
maintain genome integrity. The DNA damage checkpoint induces cell cycle arrest
during interphase in response to DNA damage or stalled replication. The spindle
assembly checkpoint (SAC) causes metaphase arrest in response to kinetochores
that are not attached to microtubules during mitosis. However, cleavage-stage
embryos forgo checkpoint function in their commitment to rapid cell proliferation.
Little is known about how checkpoints are suppressed during cleavage stages or
how they are acquired at the MBT. The following section reviews our current knowl-
edge of SAC and DNA damage checkpoint signaling prior to the MBT.
9.2.3.1 The DNA Damage Checkpoint in Cleavage Cycles
In somatic cells, DNA damage activates two phosphoinositide 3-kinase-related pro-
tein kinases (PIKKs): ataxia-telangiectasia mutated (ATM) and ATM and RAD3-
related (ATR). ATM and ATR are similar in structure and share many of the same
substrates, but are activated by distinct triggers. ATM is activated by DNA double-
strand breaks (DSBs) and ATR is activated by single-strand DNA (ssDNA) or ssDNA–
dsDNA junctions. One of the earliest consequences of DNA damage is phosphorylation
of Serine 139 on the histone variant H2AX (γH2AX) by ATM and ATR. The forma-
tion of γH2AX foci surrounding the damage site creates a docking site that recruits
9 Cell Cycle Remodeling and Zygotic Gene Activation at the Midblastula Transition