Module 4 · Time and Proliferation
Circadian Control of the Cell Cycle
The cell cycle and the circadian clock are two autonomous oscillators that share the cell. In proliferating tissues they are coupled: the circadian clock gates cell-cycle progression at specific phases of the day, so that S-phase DNA synthesis and M-phase mitosis peak at characteristic times. This gating has direct implications for cancer biology and chronotherapy.
1. Circadian Gating of G2/M
The cell cycle progresses through G1 → S → G2 → M, gated by cyclin/CDK complexes. The circadian clock primarily regulates the G2/M transition through:
- Wee1: CLOCK/BMAL1 directly transcribes Wee1 via E-box. Wee1 kinase phosphorylates CDK1 (inhibitory), blocking entry to mitosis. Wee1 oscillates; cell division occurs preferentially during Wee1 trough.
- c-Myc: represses by BMAL1. c-Myc controls cyclin D/E. Loss of BMAL1 derepresses c-Myc, driving inappropriate proliferation.
- p21/Cip1: CDK inhibitor; controlled by REV-ERB signalling.
Mouse liver regeneration after partial hepatectomy: mitotic entry is strongly synchronised to the circadian phase (Matsuo 2003). Mice with liver-specific BMAL1 knockout lose this synchrony and exhibit higher rates of aberrant mitoses. The clock thus controls not only when cells divide, but the fidelity of their division.
2. G1/S Regulation
Cyclin D1 accumulation is circadian-modulated in liver, skin, and bone marrow. NONO/PSF splice factors, both circadian-regulated, splice Cyclin D1 pre-mRNA. Mouse skin: BrdU incorporation (S phase) peaks in late afternoon in most tissues but varies by body region and activity pattern. Shift workers’ skin shows altered temporal patterns of DNA-synthesis and DNA-damage response markers — one of the mechanisms proposed for elevated skin cancer risk.
3. DNA-Damage Response Oscillates
The DNA-damage checkpoint and repair machinery are rhythmic. ATR/ATM kinase activity, BRCA1/2 expression, and nucleotide-excision-repair efficiency all vary with circadian time.
Consequence: DNA-damaging agents (UV, ionising radiation, cytotoxic chemotherapy) produce different lesion loads and different survival outcomes depending on the time of day they are delivered. In mouse studies, afternoon UV causes more lesions than morning UV because nucleotide-excision-repair activity is low in the afternoon. Human skin observations match: skin-cancer incidence correlates with circadian repair dynamics and chronic morning-vs-evening sun exposure patterns.
4. Clock Genes as Tumour Suppressors
Genetic evidence:
- Per2 knockout mice: increased spontaneous lymphoma incidence and radiation-induced tumorigenesis (Fu & Lee 2002).
- BMAL1 knockout: accelerated MYC-driven B-cell lymphoma (Puram 2016); hepatocellular carcinoma in liver-specific KO + chronic jet lag (Kettner 2016).
- Chronic jet lag in mice (repeated 8 h light shifts): accelerated tumour growth, increased spontaneous cancer incidence.
Clinical correlates: shift-work night shifts classified IARC Group 2A (WHO 2019), elevated relative risks of breast (~30%), prostate, and colorectal cancer in chronic shift workers.
5. Cancer Chronotherapy
If healthy tissue cell cycles and cancer cell cycles have different circadian phases, timed chemotherapy could exploit the difference. Francis Lévi’s clinical programme in metastatic colorectal cancer (Li 2010, EORTC 05963 trial): 5-fluorouracil + oxaliplatin infused at circadian-optimised times (5-FU peak at 04:00; oxaliplatin peak at 16:00) produced higher tumour response and reduced toxicity vs flat-infusion controls. The benefit was sex-specific (greater in men than women), highlighting unresolved biology. Chronotherapy remains a niche but growing clinical discipline — Module 7 returns to it.