January 12, 2021 | Jerry Bergman

Complexity of Cancer-Stopping Gene Regulation Described


 The Oncogene System Gets Even More Complex

by Jerry Bergman, PhD


Since the gene was identified by Danish botanist Wilhelm Johannsen in 1909, the research has moved our knowledge toward ever more complexity, a trend which makes evolutionary theory less and less credible. Gregor Mendel, the “Father of Genetics,” first published his research in 1866, but it was ignored even though he sent reprints of all 48 pages of his paper to about 100 scientists and libraries. One of the recipients was Charles Darwin, who evidently never read it.

Darwin struggled with the problem of how organisms pass traits on to their offspring. Why were some traits passed on and other traits not passed on? How and why did the parents’ traits influence the offspring? Darwin could never answer these questions, but Mendel’s work would have helped greatly to answer them. The significance of Mendel’s work was finally acknowledged only in 1900 by three European scientists, Hugo de Vries, Carl Correns, and Erich von Tschermak. In 1972, Walter Fiers and his team at Ghent University (Belgium) determined the sequence of a gene in the bacteriophage  coat protein. Gene sequencing had now begun and by now millions of genes have been sequenced.

Richard J. Roberts and Phillip Sharp discovered that genes can be split into segments, indicating that a single gene might code for several proteins. Since then research into the operations of the genome has taken off, producing hundreds of thousands of papers on genes. We learned in the 1950s that genes consist of information, not just molecules. The only known source of information is intelligence. The information in a cell is mind-boggling, adding to the reputation of a human cell as the most complex structural unit in the entire universe.

A New Gene Discovered

Several so-called gene-silencing mechanisms operate in cells to turn off protein production. These are all critical to regulating protein production levels. Like every biological process in life, tight regulation is critical. Too little of a certain protein is problematic, as is too much. Both conditions can be lethal.

The story of the new genetic finding covered here was introduced as follows: “A long-running debate over how an important gene-silencing protein identifies its targets has been resolved by researchers at Massachusetts General Hospital.”[1] The protein the gene produces is Polycomb repressive complex 2 (PRC2) shown in Figure 1. It helps to regulate genes by turning them on or off. Its role in gene silencing is critical throughout a person’s lifespan, from embryo formation to old age. The excitement about the discovery is due in part to its important implications for drug development and cancer treatment. The findings concern

a molecular ‘address’ that explains how the cancer-related protein PRC2 binds to RNA to silence genes. The study resolves a longstanding debate about the contradictory behavior between PRC2 and RNA. The findings could have important implications for development of drugs to treat cancer and other diseases.

Figure 1. The human polycomb repressive complex that adjusts down gene activity (Wiki Commons).

A brief digression about cancer is required to understand the significance of this discovery about the Polycomb repressive complex 2. Its link to cancer illustrates very well the theme of this review: research has increased our appreciation for the complexity of the cell.

Some Background on Cancer

I worked as a research scientist on cancer at a medical school, so have some background in this area. Cancer is a horrible disease but, fortunately, numerous complex systems have been built into the body to prevent it. They are most often successful. For example, when cells become cancerous, a healthy body’s immune system is usually able to detect and destroy the renegade cells. This is true even though the cancer cells are the body’s own cells.  Every adult has precancerous and some cancerous cells as well. It is only when the number of these cells is greater than what the immune and protection systems can handle (or if the immune system becomes weak or is damaged from poor health habits) that a person develops the disease we call cancer. Examples of poor health habits include smoking, poor diet, or exposure to high levels of radiation such as radon.

Cell growth is controlled by two systems, one that causes cell growth and cell division, and another that regulates cell growth. Cancer is a result of mutational damage to this system. In short, gene breakage causes loss of cell-growth control. As a consequence, cancer cells grow unabated, causing the cells to pack tightly, resulting in hard masses called tumors.[2] All genes that facilitate cell growth are called  proto-oncogenes; those that regulate cell growth are called tumor suppressor genes.

Proto-oncogenes stimulate or cause cell division during periods of normal growth, such as occurs when a child is growing up. These genes, when damaged, are called oncogenes. Oncogenes cause cancer because the protein they produce is not regulated, so they continuously send a message to the cell to divide.[3] Normally, these oncogenes send a message to the cell nucleus to divide only when they receive a message from an outside control center.[4]

What happens if an oncogene’s on switch becomes jammed? It’s like a broken switch that causes a motor to run until the motor burns out. An example is the RAS gene which is commonly damaged in pancreatic cancer and many other cancers. When RAS genes are damaged, cells grow uncontrollably and evade the apoptosis death signals which are designed to kill damaged cells. RAS mutations also make cells resistant to some cancer therapies.

On the other side of gene regulation are the tumor suppressor genes. These regulate cell growth, and also serve to inhibit cell division if the cell or the regulation control system is damaged. An example of a tumor suppressor gene is p53, named because the p53 gene protein weighs 53 kilodaltons, equal to 53 thousand hydrogen atoms. See Figure 2 for an illustration of this gene. Many proteins are named using this system because the name also conveys the protein size. Called the “guardian of the genome,” about half of all cancers involve a broken p53 system. It evaluates the genome in the cell cycle, and directs repairs in the cell if needed. It can destroy the cell if the repairs required are too great.

Figure 2. The p53 molecule, the “guardian of the genome.” All of its bonds and atoms must be in the proper place for it to function properly. The total mass is equal to 53 thousand hydrogen atoms (Wiki Commons)

The New Research

The mystery about polycomb repressive complex 2 (PRC2) remained “unsolved for years: How was the protein able to target specific genes?”[5] Jeannie Lee, MD, Ph.D., proposed ribonucleic acid (RNA) acts a recruiter for PRC2. Lee and her colleagues demonstrated that RNA acts as a “free agent” that binds to PRC2. Many kinds of RNA exist, including messenger RNA (mRNA) and transfer RNA (tRNA). Thus, they found yet another role for RNA: it targets PRC2 to act on a specific gene in order to silence it.[6]

Lee pictures PRC2 as a letter that needs to be delivered by a mail carrier, but lacks an address. The address is written on the RNA. The researchers identified unique RNA sequences that allow it to be recognized by PRC2. The RNA address then guides PRC2 to a specific gene location. PRC2 and RNA often interact at genes that are not silenced because PRC2 acts like a light dimmer switch. If the Polycomb-RNA interaction were removed, the genes would be fully activated and would shine brightly.


Yet another complex system, PRC2 in the cell, adds to the scores of other systems previously elucidated by research into the properties of genes. To help understand its function in the cell, analogies like dimmer switches are used. As a person reads this, one is forced to wonder how the PRC2 molecule knows where to go, how to interact with the gene, and do what to is supposed to do? It is designed (programmed) to do these functions, but who programmed it? How could evolution by natural selection change that structure to move the system toward its important function? According to Darwin, natural selection works only by slow, gradual variations which are supposed to move the molecule toward a useful function one step at a time. But it is inept to produce a functional PRC2 molecule because its interactions with its partners are irreducibly complex. PRC2 cannot take part unless it is built according to rigid specifications.

PRC2 is an enormously complex molecule, as shown in Figure 1, and all of the bonds and atoms shown must be in the proper place for it to function. It will not function properly—or at all—until all of its bonds and atoms are properly assembled. If even minor alterations are made, it will not work. The DNA code that makes the PRC2 molecule has to be in place, too, as does its scheme to reduce protein production by a certain amount on a sliding scale while not blocking the protein’s operation. In addition to that, PRC2 would be useless unless another system that makes the RNA address to guide it to a specific gene location were already in place. That system, too, had to be set up and regulated beforehand.

All these factors are involved in just one of many cellular systems with multiple subsystems that have to function properly in a living cell simultaneously. The whole picture absolutely exudes design.


[1] Science Daily. 2021. Study resolves long-running controversy over critical step in gene silencing, January 4.. https://www.sciencedaily.com/releases/2021/01/210104170101.htm.

[2] Bergman, Jerry. 1999. Tumor Markers in Cancer Treatment. Master of Science in Biomedical Science Dissertation. Toledo, OH: Medical College of Ohio.

[3] Cooper, Geoffrey. 1995. Oncogenes. Boston: Jones and Bartlett Publishers.

[4] Sonnenschein, Carlos, and Ana M. Soto. 2020. Over a century of cancer research: Inconvenient truths and promising leads, PLOS Biology 18(4):e3000670, April 1.

[5] Science Daily. 2021. Study resolves long-running controversy over critical step in gene silencing, January 4.  https://www.sciencedaily.com/releases/2021/01/210104170101.htm.

[6] Davidovich, Chen. 2013. Promiscuous RNA binding by polycomb repressive complex 2. Nature Structural & Molecular Biology 20(11):1250–1257, September 28.

Dr. Jerry Bergman has taught biology, genetics, chemistry, biochemistry, anthropology, geology, and microbiology for over 40 years at several colleges and universities including Bowling Green State University, Medical College of Ohio where he was a research associate in experimental pathology, and The University of Toledo. He is a graduate of the Medical College of Ohio, Wayne State University in Detroit, the University of Toledo, and Bowling Green State University. He has over 1,300 publications in 12 languages and 40 books and monographs. His books and textbooks that include chapters that he authored are in over 1,500 college libraries in 27 countries. So far over 80,000 copies of the 40 books and monographs that he has authored or co-authored are in print. For more articles by Dr Bergman, see his Author Profile.

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