Advanced cellular biology
Week 4- Circadian clock
Circadian gating of DNA damage responses. Major cellular response pathways to DNA damage including DNA repair, DNA damage checkpoints, apoptosis, and transcriptional reprogramming are gated by the circadian clock.
SCN: suprachiasmatic nucleus is in anterior of hypothalamus
A conserved network motif of circadian clocks involves a transcription–translation negative-feedback loop with delay. In mammals, circadian clocks are cell
autonomous and are found in all major organ systems and tissues of the body. A hierarchical organization exists in which the hypothalamic suprachiasmatic
nucleus (SCN) acts as a master pacemaker to synchronize behavioural and physiological rhythms throughout the body.
Circadian clock regulation of DNA repair
Model for the circadian regulation of XPA and excision
repair by the clock and the ubiquitin−proteasome system.
Coupling of the Circadian clock with DNA damage signaling pathways
DNA damage is detected by the ATR and ATM sensor kinases and is
transmitted to signal transducing kinases ; Chk1 and Chk2
These kinases phosphorylates effector proteins leading the
inhibition of Cdc2 and Cdc 1 and Cdk2
Two models for coupling the circadian clock to the cell
cycle/checkpoint response. (A) Serial coupling. DNA repair, checkpoint activation, cell cycle regulation, and cellular proliferation are gated by the clock. Conversely, the cell cycle influences the circadian cycle
(B) Direct coupling. The core circadian clock proteins participate in the signaling pathways in response to UV and IR.
Coupling of the Circadian clock with ATR- Chk-1 damage signaling
Coupling of the Circadian clock with ATM-Chk-2 damage signaling
Effect of sh-RNA-per1 on ATM, TP53 and C-MYC mRNA and Protein Expression in U343 Human Glioma Tumor Cell Lines Following Irradiation.
Clock control of apoptosis
Circadian control of carcinogenesis
The capacity for excision repair in mouse skin oscillates with circadian rhythm
The control was not irradiated;
the AM group was irradiated at 4 a.m. (XPA minimum), and the PM
group was irradiated at 4 p.m. (XPA maximum).
Effect of the circadian clock on repair and cancer. XPA protein
levels in epidermis
(line plot) over the entire cycle and invasive cancer caused by UV at 4 a.m. and 4 p.m. (bar graph) are shown
Circadian control of apoptosis and cancer treatment
Preferential killing of cancer cells relative to normal cells is the predominant rationale in all therapeutic approaches.
A major mechanism of drug-induced cell killing is programmed cell death (apoptosis).
Contrary to expectation, the p53−/−Cry1/2−/− mice
had a reduced age-adjusted incidence of cancer and lived 1.5- fold longer than the p53−/
− mice
The combination of Cry mutation with
the ink4a−/−;ras(V12G) mutation did not affect the melanoma incidence and hence, it was
concluded that in this genetic background, Cry mutation has no moderating effect on cancer incidence or progression.
Circadian clock and chemothreapy
oxaliplatin had only marginal effects on p53−/− tumors but caused massive apoptosis and tumor
regression in p53−/
−;Cry1/2−/− tumors.
the absence of p53, p73 (of the p53, p63, p73 family) becomes the major driver of apoptosis and p73 is highly
upregulated after DNA damage as a second-order clock-
controlled gene.
