One of Aziz Sancar and His Team's Most Remarkable Discoveries: Circadian Rhythm, Cancer and Chemotherapy!

Circadian rhythm is, briefly, our body's clock. It encompasses and regulates biochemical and psychological behaviors over a daily 24-hour period. Long known scientifically, its operation at the cellular level was discovered in recent years by scientists led by our Nobel laureate Aziz Sancar. His team went further, explaining its relationship with DNA repair and possible effects on cancer treatment.

Circadian rhythm lets us sleep and wake at appropriate times. It helps control blood pressure, body temperature, heart rate and the sleep-wake cycle. Bodily functions follow this rhythm. In mammals, the suprachiasmatic nucleus at the front of the brain sets the main rhythm through light reaching the retina. It also synchronizes tissues. Without this nucleus, tissues retain their individual rhythms but lose synchronization.

Let Us Recall “What Is Cancer?”

Cells forming our organs renew, multiply and die under programmed self-control. Genetic changes disrupting this can produce excessive multiplication. Altered cells escaping control can grow independently and spread locally or to distant organs (metastasis). Such uncontrollably growing, locally spreading or metastatic cell groups are called cancer.

Cancer cells therefore arise from our own cells. Chemotherapy aims to damage them, but healthy cells are destroyed too, generally causing side effects such as nausea, vomiting and hair loss. Many drugs kill cells and stop multiplication by disrupting DNA. Meanwhile, our body has mechanisms repairing damaged DNA, protecting against diseases. The same mechanism also repairs cancer DNA that chemotherapy tries to damage. This is the problem: the body unknowingly repairs and renews cells we are trying to kill.

Aziz Sancar's team becomes relevant here. They discovered that the DNA repair system also follows circadian rhythm. Accordingly, DNA repair is very slow at certain times and very fast at others during the day.

The main implication is that treatment when DNA repair is slowest offers a dosing advantage and helps achieve maximum effect.

To Examine This Valuable Study by Topic

• Circadian Rhythm and the DNA Damage Response
  There are 3 main DNA damage response networks influenced by circadian rhythm: DNA repair, DNA damage checkpoints and apoptosis (programmed, controlled cell death).
  • Circadian Regulation of DNA Repair
    DNA, carrying genetic information, frequently suffers chemical damage for various reasons, repaired by different systems. One mechanism is nucleotide excision repair (NER), containing 6 repair factors functioning sequentially. A segment around the damage, 24-32 nucleotides (DNA units) long, is removed, and enzymes such as DNA polymerase fill the gap to correct damage.
    
    This mechanism's activity varies with circadian rhythm, being greater by day than at night. Daily changes should be considered in cancer treatment as in many diseases. Chemotherapy damages tumor DNA, while repair mechanisms restore it, reducing treatment effectiveness. Our main aim is to attack tumor cells when repair activity is lowest.
  • DNA Damage Checkpoints
    Errors may occur during cell division. Checkpoints prevent them, protecting DNA and ensuring its intact transmission to daughter cells.
    
    Circadian rhythm regulates checkpoints in two ways: controlling checkpoint protein production and involving circadian-regulating proteins in checkpoint responses.
  • Circadian Rhythm and Apoptosis
    Apoptosis is a principal form of programmed, controlled cell death, the normal means of removing unneeded or abnormal cells. A series of molecular processes causes death and is necessary and beneficial for the organism's life cycle. For example, cells between developing embryonic fingers must initiate apoptosis so the fingers can separate.
    
    Cells respond to circadian disruption with DNA damage. Increased apoptosis sensitivity may alter cancer treatment effectiveness. Tumors with Cry1/2 (circadian-regulating genes) and p53 (tumor suppressor) mutations are more chemotherapy-sensitive than tumors with only p53 mutation. Using Cry (cryptochrome) gene inhibitors may increase chemotherapy effectiveness.
• Circadian Rhythm and Cancer
  Many diseases, including cancer, vary with circadian rhythm. Scheduling treatment accordingly may improve results. This led to the concept of chronotherapy.
  Chronotherapy means giving treatment at particular times of day to maximize drug benefit.
  
  Chemotherapy effectiveness can also be timed, called chronochemotherapy. Because most cancer drugs act through tumor DNA damage, clearer understanding of circadian rhythm and DNA damage will broaden its use.
  
  Circadian rhythm may aid prevention as well as treatment. Aziz Sancar emphasized this for skin cancer, showing that it may identify times when sun exposure increases or reduces risk.

Let Us Summarize in the Words of Aziz Sancar, Our Pride and the First Turkish Scientist Awarded a Nobel Prize:

''In mouse research, morning UV exposure produced a cancer risk compared with late-afternoon exposure at 4 o'clock that was 5 times higher. Thus, mouse skin cancer risk is lower in the evening. These results are reversed in humans. We can therefore suggest lower skin cancer risk in the morning for people. Morning sun exposure is less risky than midday or afternoon. However, we must first conduct human experiments to state this definitively.''