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here, p53 is localized mainly in the cytoplasm (
Aladjem et al., 1998
), and
upon induction of DNA damage, p53 is translocated to the nucleus where
it can suppress Nanog expression and thereby interfere with ESC self-
renewal (
Aladjem et al., 1998; Lin et al., 2005; Solozobova, Rolletschek,
& Blattner, 2009
). Therefore, rather than promoting genome maintenance
by instructing cells to slow down cell cycle in order to repair damage, p53
can instruct ESCs with DNA damage to differentiate. Recent studies using
other primate and nonprimate ESCs caution that regulation of the G1- to
S-phase transition may vary in different species (
Neganova et al., 2009
)
and that human ESCs may have a partly functioning G1/S checkpoint
(
B´rta et al., 2010
).
At the molecular level, many cell-cycle regulators that, in differentiated
cells, show a characteristic oscillation in activity, either do not oscillate in
ESCs or do so in a much more muted way (
Ballabeni et al., 2011
). In somatic
cells, different CDKs show sequential peaks of activity restricted to specific
stages, allowing cell cycle to progress in an ordered manner (
Fig. 7.2
, top;
reviewed in
Bloom & Cross, 2007
). CDK activities are closely linked
to anaphase promoting complex/cyclosome (APC/C) activity, which is
responsible for degradation of key cell-cycle regulators such as cyclins and
geminin (reviewed in
Bloom&Cross, 2007; Peters, 2006
). Geminin inhibits
CDT1, a factor that induce DNA synthesis, between S-phase and meta-
phase-anaphase transition (
Wohlschlegel et al., 2000
). Such inhibition pre-
vents excess rounds of DNA synthesis. In mouse ESCs, geminin is present
throughout most of the cell cycle (
Yang et al., 2011
). The boundaries
restricting CDK activity in ESCs are therefore not distinct (
Fig. 7.2
, bot-
tom). Other key regulators are also expressed at very high levels compared
to differentiated cells, which may also contribute to the unique cell-cycle
structure of ESCs (
Fig. 7.2
,
Ballabeni et al., 2011; Fujii-Yamamoto, Kim,
Arai, & Masai, 2005; White et al., 2005; Yang et al., 2011
).
3. METHODS FOR RESTORING PLURIPOTENCY
The identity and transcriptional properties of differentiated cells
(or their immediate precursors) are normally preserved through cell division.
This mitotic inheritance can, however, be subverted under certain conditions.
For example, during
in vivo
regeneration, transdifferentiation and dediffer-
entiation, cell lineage stage and affiliation are reset. In addition, experi-
mental reprogramming can be used to encourage cells to revisit or
adopt new epigenetic and transcriptional programs. Currently,
three
