M03.02.04 DNA Repair

DNA can be damaged by various factors such as chemicals, radiation, and errors during replication. To maintain genomic integrity, cells have evolved multiple DNA repair systems. Proper DNA repair is crucial to prevent mutations, which can lead to cancer. Most DNA repair mechanisms operate during the G1 phase, while mismatch repair occurs in the G2 phase to correct replication errors.

Types of DNA Damage and Repair Mechanisms

1. Thymine Dimers (G1 Phase)
   • Cause: UV radiation.
   • Recognition/Excision Enzyme: Excision endonuclease (deficient in Xeroderma pigmentosum).
   • Repair Enzymes: DNA polymerase and DNA ligase.
2. Mismatched Bases (G2 Phase)
   • Cause: DNA replication errors.
   • Recognition/Excision Enzyme: Mutations in hMSH2 or hMLH1 genes initiate defective repair.
   • Repair Enzymes: DNA polymerase and DNA ligase.
   • Condition: Hereditary Nonpolyposis Colorectal cancer (HNPCC).
3. Cytosine Deamination (G1 Phase)
   • Cause: Spontaneous or heat-induced.
   • Recognition/Excision Enzyme: Uracil Glycosylase and AP endonuclease.
   • Repair Enzymes: DNA polymerase and DNA ligase.

Detailed Repair Processes

1. Repair of Thymine Dimers

UV light causes the formation of thymine dimers, which interfere with DNA replication and gene expression. Thymine dimers are repaired through nucleotide excision repair (NER):

• Excision Endonuclease (Excinuclease): Makes nicks in the DNA backbone on both sides of the thymine dimer and removes the defective oligonucleotide.
• DNA Polymerase: Fills in the gap using the undamaged strand as a template.
• DNA Ligase: Seals the nick in the repaired strand.

2. Base Excision Repair (BER)

Cytosine deamination converts cytosine to uracil, which is recognized and removed by BER:

• Uracil Glycosylase: Removes the uracil from DNA.
• AP Endonuclease: Removes the damaged sequence.
• DNA Polymerase: Fills in the gap.
• DNA Ligase: Seals the nick in the repaired strand.

3. Mismatch Repair (MMR)

During DNA replication, mismatched bases are corrected by MMR in the G2 phase:

• Recognition: MSH2 and MLH1 proteins detect mismatched bases.
• Repair Enzymes: DNA polymerase corrects the mismatch, and DNA ligase seals the repaired strand.

Diseases Associated with DNA Repair Defects

1. Xeroderma Pigmentosum (XP)

• Cause: Deficiency in exonuclease enzyme.
• Symptoms: Extreme sensitivity to UV light, excessive freckling, multiple skin cancers, and corneal ulcerations.

2. Hereditary Nonpolyposis Colorectal Cancer (HNPCC or Lynch Syndrome)

• Cause: Mutations in hMLH1 or hMSH2 genes impairing mismatch repair.
• Symptoms: Predisposition to Colorectal cancer and other types of cancer due to microsatellite instability.

Key Genes in DNA Repair and Cell Cycle Control

• p53: Prevents damaged cells from entering the S phase; mutations lead to Li-Fraumeni syndrome and many cancers.
• ATM: Essential for p53 activity; inactivation leads to ataxia telangiectasia with sensitivity to x-rays and lymphoma risk.
• BRCA1 and BRCA2: Involved in repair; mutations increase the risk of breast, prostate, and ovarian cancers.
• Rb: First cloned tumor suppressor gene; regulates cell cycle by binding E2F transcription factor.

Summary of DNA Repair Mechanisms

Understanding these repair mechanisms is crucial in the study of genetics, oncology, and molecular biology, as defects in these processes are directly linked to the development of various cancers and genetic disorders.