DNA Repair and Cancer

DNA Repair and Cancer

• Inherited mutations in DNA repair genes are strongly associated with high cancer risks in humans.
• Bloom's syndrome is characterized by sunlight hypersensitivity and a high incidence of malignancies (e.g., leukemia) due to defects in DNA ligase I and RecQ helicase.
• Hereditary nonpolyposis colorectal cancer (HNPCC) is strongly associated with specific mutations in the DNA mismatch repair pathway.
• BRCA1 and BRCA2 are associated with breast cancer and are involved in multiple DNA repair pathways, including NHEJ and homologous recombination.

Cancer Therapy

• Cancer therapy, such as chemo- and radiotherapy, works by overwhelming the cell's capacity to repair DNA damage, leading to cell death.
• Rapidly dividing cells, such as cancer cells, are most affected by cancer therapy.
• Side effects also occur in non-cancerous cells, particularly those that divide rapidly, such as stem cells in the bone marrow.
• Modern cancer treatments aim to localize DNA damage to cancer cells and tissues using physical or biochemical means.

DNA Damage

• DNA damage occurs due to normal metabolic activities and environmental factors, such as UV light and radiation.
• Approximately 1 million individual molecular lesions occur per cell per day.
• There are two main types of DNA damage: endogenous (e.g., reactive oxygen species, ROS) and exogenous (e.g., UV, x-rays, gamma rays).

Types of DNA Damage

• Five main types of DNA damage occur due to endogenous cellular processes:
  • Oxidation of bases
  • Alkylation of bases (methylation)
  • Hydrolysis or bases (deamination, depyrimidination, depurination)
  • Bulky adduct formation
  • Mismatch of bases
• Exogenous agents can cause DNA damage, including:
  • UV-B light (pyrimidine dimers)
  • UV-A light (free radicals)
  • Ionizing radiation (DNA breaks)
  • Thermal disruption (depurination, single-strand breaks)
  • Industrial chemicals (e.g., vinyl chloride, hydrogen peroxide)
  • Environmental chemicals (e.g., polycyclic hydrocarbons)

DNA Repair Mechanisms

• DNA damage alters the spatial configuration of the helix, which is detected by cells.
• DNA repair molecules can bind at or near the damage site, inducing a cascade of reactions that form a complex to repair DNA.
• There are several repair mechanisms for single-strand breaks, including:
  • Base excision repair
  • Nucleotide excision repair
  • Mismatch repair

Single-Strand Break Repair

• Base excision repair repairs damage caused by oxidation, alkylation, hydrolysis, or deamination.
• Damaged nucleotides are removed by DNA glycosylase, resynthesized by DNA polymerase, and sealed by DNA ligase.
• This process occurs constantly.
• Nucleotide excision repair recognizes bulky, helix-distorting lesions and removes incorrect bases using 3'->5' exonuclease activity.