DNA Repair and Cancer

Study Notes

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.

Description

Learn about the associations between DNA repair gene mutations and cancer risks, including Bloom's syndrome, HNPCC, and BRCA1/2. Test your knowledge on the role of DNA repair pathways in human cancer.