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oscillation of NAD þ has numerous effects in the cell which includes its
ability to feed back into the clock system via CLOCK:BMAL1-mediated
gene transcription. Mitochondrial NAD þ is used as a carrier molecule for
oxidation-reduction reactions and as such is essential for cellular energy
balance. Electrons and a hydrogen atom removed from a substrate molecule
are picked up by NAD þ and ultimately used to generate additional ATP,
driving ATP-dependent reactions. NAD þ is generated from niacin and par-
ticipates as a coenzyme in many cellular dehydrogenase reactions, including
b -oxidation of fatty acids and the Krebs cycle. Adding to its role in ATP
generation, NAD þ also provides the ADP-ribose necessary for ADP-
ribosylation of some proteins. Increases in the activity of the NAD þ -
dependent ribosylating enzyme, poly(ADP-ribose) polymerase-1 (PARP-
1), can deplete cellular NAD þ pools, ultimately causing damage and cell
death. 90-92 PARP-1 may be an important player in the circadian influence
of transcription via chromatin modification. PARP-1 has been shown to
have a direct role in the regulation of chromatin structure through the mod-
ulation of the histone demethylase KDM5B. 93 PARP-1 is thought to allow a
permissive chromatin state such that proper loading of the RNA Pol II
machinery can take place. This is accomplished by PARP-1-mediated inhi-
bition of the histone demethylase KDM5B. As a modifier of PARP-1 but
also as an activator of SIRT1, the contribution of NAD þ to cellular meta-
bolic homeostasis is mediated in large part through its role in gene expres-
sion. Figure 2.4 summarizes the pleotropic roles of NAD þ in the cell.
The small molecule cyclic ADP-ribose (cADPR) is made from NAD þ
by ADP-ribosyl cyclases, and it has also been reported to oscillate in a cir-
cadian fashion. cADPR is a ligand for type-3 ryanodine receptors, which are
receptors important for generating cytosolic calcium in plants and animal
cells. 94 The dependence of this metabolite on the levels of cellular NAD þ
levels provides another example of how oscillations in metabolites partici-
pate in the circadian clock system and thereby integrate cellular metabolism
into cellular timekeeping.
In addition to NAD þ , a number of other metabolites are important for
epigenetic changes at chromatin, particularly when it comes to modification
of histone tails. Figure 2.3 depicts the many modifications that can take place
on the tail of H3 and shows just a small number of the many metabolites that
assist in these marks.
The importance of epigenetics in gene expression extends to that of
nuclear hormone receptors. While the expression of numerous nuclear hor-
mone receptors oscillates, the expression of some does not. Regardless of
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