DNA Mutation, Repair and Cancer

Mutation, DNA Repair, and Cancer Overview

• Cigarette smoke contains chemicals that can mutate DNA, potentially leading to lung cancer.

Point Mutations

• Base substitution involves replacing one base in the DNA sequence with another.
• Adding or deleting a single base pair alters the DNA sequence.

Gene Mutations and Amino Acid Sequences

• Silent mutations do not change the amino acid sequence due to genetic code degeneracy.
• Missense mutations result in a single amino acid change in a polypeptide; altered function depends on the amino acid's properties.
• Nonsense mutations change a codon to a stop codon, resulting in a truncated polypeptide.
• Frameshift mutations involve nucleotide addition or deletion, leading to a different amino acid sequence downstream.

Gene Mutations Outside of Coding Sequences

• Mutations in the promoter sequence can affect transcription rate by either enhancing or inhibiting it.
• Mutations can occur in regulatory elements or operator sites.
• Mutations can alter operator DNA, preventing repressor protein binding.

Germ-Line vs. Somatic Cell Mutations

• Germ-line mutations affect germ cells, leading to the mutation being transmitted to all cells in the body.
• Somatic mutations affect somatic cells, influencing only a small group of cells.
• Germ-line mutations can occur in sperm or egg cells, while somatic mutations appear early or late in development.
• Germ-line mutations are heritable, while somatic mutations are not.

Causes of Mutations

• Spontaneous mutations arise from abnormalities in biological processes, with rates varying across species and genes.
• The background mutation rate is about one mutation per million genes.
• Induced mutations are caused by environmental agents, occurring at a higher rate than spontaneous mutations.
• Mutagens, such as chemical or physical agents like smoking, X-rays, and UV light, alter DNA structure.

Mutagens and DNA Structure

• Base analogs can substitute into DNA, disrupting base pairing and distorting the helix.
• Benzopyrene, present in cigarettes and charbroiled food, is a mutagen.
• Ionizing radiation like X-rays and gamma rays creates free radicals that can cause DNA deletions/breaks.
• Nonionizing radiation (UV rays) has less energy but can induce thymine dimers, potentially causing gaps or base misincorporation.

DNA Repair Mechanisms

• There must be ability to repair DNA damage to minimize mutations.
• Detection and repair of damage are essential steps.
• Direct repair involves an enzyme correcting an incorrect DNA structure.
• Nucleotide excision repair (NER) removes and replaces a section of DNA containing an abnormal nucleotide.
• Methyl-directed mismatch repair detects base pair mismatches, removing/replacing the surrounding DNA strand.

Nucleotide Excision Repair (NER)

• NER is the most common DNA repair system.
• It removes several nucleotides around damaged DNA.
• Intact DNA strands serve as templates for resynthesis.
• NER is found in all eukaryotes and prokaryotes.

Cancer Overview

• Cancer is a disease of multicellular organisms characterized by uncontrolled cell division.
• Approximately 1.5 million Americans diagnosed with cancer annually, with over 0.5 million dying from the disease.
• About 10% of cancers are due to inherited traits, while most cancers (~90%) are not genetically inherited.

Carcinogens and Cancer

• About 80% of human cancers are related to carcinogen exposure.
• Mutagens like UV light and cigarette smoke can lead to somatic cell genetic changes.
• DNA alterations > gene expression > cell division > cancer.
• Cancers originate from a single cell, with its offspring mutating and growing abnormally.

Tumors

• Tumors are excessive cell growth with no purpose, may begin as benign or precancerous, may become malignant.

Cancer Stages

• Malignant cancers are defined by a loss of normal growth regulation.
• Cancer cells can invade healthy tissue; and migrate with metastasis to other body parts.
• Untreated malignant cells can eventually cause death.

Oncogenes

• Growth factors regulate cell division.
• Mutations cause genes to become overactive, promoting uncontrolled cell growth.
• Mutations in cell growth signaling proteins can create oncogenes, leading to abnormally high activity.
• Oncogenes contribute to uncontrolled cell growth by keeping the cell division signaling pathway in “on” position.
• The amount of gene product or gene hyperactivity contributes to some cancers.

Oncogenes: Ras

• Ras protein, an intracellular signaller, hydrolyses GTP.
• Promotes cell division when GTP is bound.
• Ras mutations can decrease GTP ability-hydrolyzation, keeping the signal pathway running constantly, promoting growth.

Proto-oncogenes

• Proto-oncogenes are a normal gene that, when mutated, can become an oncogene.
• Common genetic changes leading to oncogene conversion include:
  • Missense mutations and translocations
  • Gene amplification
  • Specific chromosomal translocations

Tumor Suppressor Genes

• Tumor suppressor genes normally prevent cancerous growth.
• Their functions include maintaining genome integrity by monitoring DNA damage, using check point proteins.
• They also control inhibiting cell division, preventing accelerated division and tumor formation.

Loss of Tumor-Suppressor Gene Function

• Tumor-suppressor gene function can be lost in three common ways:
  • Mutation with the gene to inactivate it
  • Chromosome loss if missing the chromosome carries the tumor-suppressors
  • Abnormal methylation of CpG islands near tumor-suppressor promoter regions.

Tumor-Suppressor Genes: Checkpoint Proteins

• Cyclins and cyclin-dependent protein kinases (cdks) advance a cell through the cell cycle phases.
• The p53 tumor suppressor gene detects DNA damage.
• About 50% of human cancers are associated with p53 gene defects.
• There is a G1 checkpoint:
  • DNA damage may prevent a cell from progressing from G1 to S phase
  • If DNA is repaired, a cell can then continue.

Cancer: A Series of Changes

• Cancer usually requires multiple genetic changes in the same cell.
• It begins with a benign alteration that leads to malignancy as additional mutations accumulate.
• The accumulation of genetic changes makes malignancy challenging to treat.