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site and seems to determine its intracellular disposition (Lopez-Girona et al., 1999).
Toyoshima-Morimoto et al. (2002) implicated the phosphorylation of a serine resi-
due (Ser198) in a nuclear export signal sequence of human Cdc25C in promoting its
nuclear localisation. One can speculate that possibly Rad24/25 (14-3-3) might inter-
fere with Cdc25 localisation. As pointed out by Ford et al. (1994) in Rad24 (−/−),
mutants cells show premature G2-M progression.
Do 14-3-3 Proteins Participate in DNA Repair?
The expression of some 14-3-3 proteins is inducible by p53 in response to DNA dam-
age, suggesting that they might possess DNA repair function. From this arises the
possibility that 14-3-3 proteins might be involved in generating drug resistance. The
cytotoxicity of DNA damaging drugs is alleviated by DNA repair of which there are
several pathways. Inhibition of repair of DNA damage potentiates the effects of cyto-
toxic drugs. DNA damage induces PARP (poly [ADP-ribose] polymerase) activa-
tion which then participates in DNA repair. PARP participates in base excision repair
and inhibition of PARP prevents the repair of DNA lesions and enhances cytotoxic-
ity. PARP mediates an important pathway to apoptosis. This could conceivably func-
tion either dependently or independently of p53. Caspases can break down PARP,
prevent DNA repair and induce apoptosis. On the other hand, there is a view that
hyperactivation of PARP could activate AIF (apoptosis inducing factor) and apoptosis
(Yu et al., 2002), although lately PARP-independent activation of AIF has been advo-
cated (Kondo et al., 2010). PARP has also been implicated in stalled replication fork
restart. It is believed to bind to and activated by stalled forks and possibly attracts
MRE11 to promote the restart (Bryant et al., 2009). A connection with the tumour
suppressor BRCA2 also seems to subsist. Increased MRE11 levels are associated
with BRCA2 deficiency (Ying et al., 2012). This also forges a link between BRCA2
deficiency and PARP inhibition in cancer management. BRCA1 has also implications
for 14-3-3 expression, in that the former induces 14-3-3σ expression in the backdrop
of wild-type p53. Both loss of BRCA1 and reduced 14-3-3σ expression are not con-
ducive to G2-M arrest upon exposure to ionising radiation (Aprelikova et al., 2001).
Quite clearly, PARP and 14-3-3σ do suggest a potential synergistic route to the regu-
lation of cell cycle progression.
DNA repair requires the assembly of nucleosomes, a process that involves CAF-1
(chromatin assembly factor-1). The latter is able to interact with several cellular proteins,
notably for instance the ASF-1 (anti-silencing factor-1) involved in chromatin dynamics.
CAF-1 can also silence specific target genes such as Notch, tumour suppressor and cell
cycle regulator Rb proteins, and PCNA (proliferating cell nuclear antigen) (Goodfellow
et al., 2007; Ridgway and Almouzni, 2000; Moggs et al., 2000), among others. In the
present context, 14-3-3 seems to take part in many components of the DNA repair appa-
ratus. For instance 14-3-3ζ forms a complex with CAF-1 (Hoek et al., 2011).
Exonuclease 1 (Exo1) which participates in the processing of stalled replication
fork and checkpoint induction is a member of Rad2 family of nucleases involved in
DNA repair, replication and recombination. Engels et al. (2011) showed that Exo1
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