Fig. 3: Impact of the circadian clock on stress response, DNA damage control and genomic instability and stemness in GBM.

a Impact of the circadian clock on stemness in GBM. Stemness is regulated by transcriptional programs. Cancer stem cells represent a major problem in therapy because they are often resistant to treatment and are responsible for residual disease and cancer recurrence. CLOCK/BMAL1 activate the transcription of ACACA and PGM1 specifically in GBM cells, which links stemness to fatty acid synthesis, glycolysis, the TCA cycle and the pentose phosphate pathway (PPP). They are also implicated in the transcription of, or positively influence, several stemness-promoting transcription factors, specifically c-MYC, NF-κB, SOX2 and OLIG2. CRY, REV-ERBβ and RORα inhibit stemness. PER2 reduces stemness by inhibition of the WNT pathway. WNT activates the transcription factor β-catenin to promote stemness. b Impact of the circadian clock on stress response, DNA damage control and genomic instability in GBM. The circadian clock is implicated in responses to DNA damage inducers (radiotherapy, TMZ), as well as responses to oxidative and nutrient stress and hypoxia. DNA damage is induced by TMZ or irradiation. Healthy cells typically respond to DNA damage by cell cycle arrest or apoptosis. These responses are regulated by a set of proteins, most notably p53. p53 is abolished or inactivated in 84% of GBM patients, which allows them to avoid cell cycle arrest and apoptosis following DNA damage. DNA damage is promoted by PER1, PER2 and BMAL1 whereas CLOCK and CRY2 inhibit it. In more detail, PER1 and PER2 induce c-MYC, which hyperactivation leads to DNA damage, whereas CLOCK reduces c-MYC. PER2 also positively influences ATM (Ataxia Telangiectasia Mutated). Following DNA damage cell cycle arrest and apoptosis is achieved by two different pathways: the CHK1 (Checkpoint Kinase 1)/p53/p21 (Protein of 21 kDa) pathway is inhibited by CLOCK and activated by PER1 and PER2; the EGR (Early Growth Response 1)/p73 (Protein of 73 kDa) pathway is inhibited by CRY2. CLOCK/BMAL1 promotes DNA damage repair by the NF-κB/Bmi (BMI1 Polycomb Ring Finger Proto-Oncogene) and the H2AX (Histone 2 AX)/γH2AX (gamma Histone 2 AX) pathways. CLOCK is implicated in the response to nutrient stress and is repressed by miR-124 and PER1 is reduced by the UPR-protein IRE1α in response to hypoxia and nutrient stress. Clock proteins are also implicated in DNA mutations, and regulate both their abundance and specificity. CRY1, BMAL1, and RORγ are associated with a higher mutation rate and mutation hotspots in EGFR, TTN, and PTEN genes. RORα, PER1, PER2, PER3, CLOCK, REV-ERBα, and CRY2 are associated with a lower mutation rate and mutations skewed towards TP53, ATRX, IDH1, and CIC. In particular, a high mutation rate respectively high genomic instability is associated with cancer. Mutations in EGFR, PTEN, TP53 and IDH1 are highly common in GBM. The figure was created with BioRender.com.