11 March 2005

Lecture 26

Reading: Chapter 6, Chapter 8

A. Protein synthesis (The Central Dogma)

B. Genomes

C. Gene regulation

3. RNA and protein turnover

The control of transcription represents 90% or more of gene regulation in a cell. There are other processes that contribute to the activity of genes, however. The life span of mRNA molecules and proteins is one of these. Old mRNAs and old proteins tend to accumulate defects as they are used by the cell. At some point, they become non-functional and the cell recycles them. This loss of mRNA and proteins modifies the effect of their new synthesis. Thus, the observed activity of a gene is a balance between the rate of new protein synthesis and the rate at which its mRNA and protein are damaged and recycled.

4. Methylation

It has been observed that silenced genes often have methyl groups (CH₃) on their cytosine bases. It is thought that this chemical modification of these genes contributes to their silencing.

D. Mutations

A mutation is a change in the nucleotide sequence of DNA. These tend to happen during the process of gene replication prior to cell division or during repair of damage to a gene, which can be caused by radiation or some chemicals. There are many kinds of mutations, including loss of a nucleotide or a whole segment of DNA, a change in the type of nucleotide at a particular position, insertion of virus or other DNA into or near a gene, and gene rearrangements. Some mutations can lead to disease.

 1. Sickle cell disease (see page 266 and 178 in text)

A mutation in a gene can have no effect or it can cause the gene to produce altered or defective proteins. A clear case of this is the mutation that leads to sickle cell disease. People with the sickle cell mutation have an altered form of hemoglobin in their red blood cells. When oxygen is low, e.g. after exercise, the altered hemoglobin clumps into rod-like structures that deform the red blood cells, giving them an elongated, crescent shape. This shape can clog capillaries and the condition is eventually fatal.

The mutation that causes sickle cell disease is the substitution of an A for a T in the hemoglobin gene. A CTT sequence in the gene normally codes for GAA in its messenger RNA. GAA in the messenger RNA specifies the amino acid glutamic acid at a particular position in normal hemoglobin. Substitution of an A for the middle T in this sequence leads to GUA in the messenger RNA, which specifies the amino acid valine. The substitution of valine for glutamic acid at this particular position alters the chemistry of the hemoglobin such that it sticks together if it is not binding oxygen, creating sickling of the red blood cells.

The sickle cell mutation is an inherited mutation. If an individual inherits a mutated gene from one parent but a normal gene from the other parent, the normal gene makes enough normal hemoglobin that no disease is evident. If an individual inherits a mutated gene from both parents, however, they will exhibit sickle cell disease.

2. Cancer

Cancers are also caused by mutations. Cancer results from inappropriate cell divisons that produce tumors. The mutations that cause this are in regulatory genes that control cell division. Usually, several mutations must occur in a cell to allow the inappropriate cell division and growth of a tumor. Mutations that lead to cancer occur in two groups of genes that have been named "oncogenes" and "tumor suppressor genes".

Oncogenes are regulatory genes that activate genes for cell division. If they are normal, cell division occurs normally. If they are mutated such that their activity increases, inappropriate cell division can result.

Tumor suppressor genes are regulatory genes that shut down inappropriate cell division after it starts. They are part of your body's natural defense against cancer. If a tumor suppressor gene is mutated such that it no longer functions properly, cancer can begin owing to lack of tumor suppression.

 a. Oncogenes

Before mutation, oncogenes produce regulatory proteins that activate genes for cell division. Several kinds of mutations can cause oncogenes to have abnormally high activity. These include mutations that make the regulatory protein it codes for "hyperactive" (stimulate cell division too much), duplication of the oncogene by gene rearrangement such that twice the normal amount of regulatory protein is made, or gene rearrangement such that the oncogene comes under control of the wrong promoter and makes too much protein.

b. Tumor suppressor genes

In contrast to oncogenes, cancer-causing mutations in tumor suppressor genes negate rather than enhance their function. Tumor suppressor genes are of three kinds: DNA repair genes that fix mutations before they can cause problems, regulatory genes that inactivate cell division genes when cell division is inappropriate, and suicide genes that trigger cell death if cell division is inappropriate. One of the genes for cell suicide is called p53. The p53 gene has been observed to be mutated in half of all tumor cells. p53 appears to be of great importance to preventing inappropriate cell division.