The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 243

with ATM and ATR suppress cyclin-dependent kinase (CDK) activity and
activate CKIs such as p21 WAF1/CIP1 in a p53-dependent manner. 174,224 Inhi-
bition of CDKs and activation of CKIs lead to arrest of cell cycle progression at
the G1/S, intra-S, or G2/M checkpoints to allowDNA damage repair. 253,254
ATM/ATR signaling also enhances DNA repair by transcriptionally and post-
transcriptionally activating DNA repair genes and by recruiting repair factors
to the sites of damage. Activation of p53 by ATM/ATR signaling in response
to genomic DNA damage often leads to p53-mediated apoptosis ( Fig. 9.1 ) . 255
A large number of key players in DNA replication, recombination, and
repair have been identified as clock-controlled genes in mice. 7,11-14 Some
of these genes, such as Xeroderma pigmentosumA (XPA) that plays an essen-
tial role in nucleotide excision repair, are deregulated in Cry1 / ; Cry2 /
mice, which correlates with a dampened circadian rhythm in nucleotide exci-
sion repair after UVB irradiation in Cry1 / ; Cry2 / epidermis. 256,257 The
evidence of direct involvement of Cryptochromes in DNA damage repair in
mammals is still missing, although Cryptochromes are structurally related to evo-
lutionarily conserved DNA photolyases that catalyze light-dependent DNA
repair in plants. 258 However, mammalian CLOCK may play a direct role
in DNA damage repair because it directly locates to the sites of g -radiation-
induced DNA double-strand breaks. 158 PER1 was found directly interacting
with ATM and CHK2 in response to g -radiation-induced DNA damage.
Overexpression of PER1 in human cancer cells sensitizes cells to radiation-
induced apoptosis by activation of Myc -mediated pro-apoptotic pathways. 82
The human CRY2 has been reported to interact with ATR and CHK1 to
regulate intra-S checkpoint function in UV-induced DNA damage response
via Timeless (TIM), a natural partner of PER in Drosophila and is necessary for
maintaining the robustness of the mammalian central clock. 175,259 The role for
BMAL1 in DNA damage response is shown by a recent study in which
knock-down Bmal1 expression abolishes g -radiation-induced p53 activation
as well as p53-dependent p21 WAF1/CIP1 induction in human colorectal carci-
noma cells. 69 All core circadian genes studied are activated by exogenous
DNA damage agents such as g -radiation in peripheral tissues following a
time-dependent profile over a 24-h period in mice. Wild-type mouse thymo-
cytes display a time-dependent response to g -radiation-induced apoptosis
in vivo , while loss of function in Per2 leads to resistance to radiation-induced
apoptosis in thymocytes throughout a 24-h period and an increased risk of
radiation-induced lymphoma in Per2 m/m and Per2 / mice. 29,124,260,261 Thus,
the potentiation of the molecular clock to respond to DNA damage agents
varies at different times during a day and plays a key role in determining
the outcomes of DNA damage response.