DNA Repair Mechanisms

Introduction to DNA Repair Mechanisms

• Biological macromolecules like DNA, RNA, and proteins are susceptible to chemical alterations due to environmental damage or synthesis errors.
• DNA's integrity is vital to cell survival and reproduction, so it has high-fidelity replication systems and repair systems to correct DNA damage.

Types of DNA Damage

• Common forms of DNA damage include:
• Missing, altered, or incorrect bases
• Bulges due to deletions or insertions
• UV-induced pyrimidine dimers
• Strand breaks at phosphodiester bonds or within deoxyribose rings
• Covalent cross-linking of strands

Types of DNA Repair Systems

• There are four main types of DNA repair systems:
• Mismatch repair
• Base-excision repair
• Nucleotide-excision repair
• Direct repair

Mismatch Repair (MMR)

• MMR corrects mismatches left after replication by distinguishing between the old (template) strand and the newly synthesized strands.
• The cell tags the template DNA with methyl groups to distinguish it from newly synthesized strands.
• The MMR system includes at least 12 protein components that function in strand discrimination or repair.
• The process involves four phases: recognition of a mismatch, recruitment of repair enzymes, excision of the incorrect sequence, and resynthesis using the parent strand as a template.

Base-Excision Repair (BER)

• BER is a major pathway for repairing damages caused by oxidation, alkylation, hydrolysis, depurination, and deamination.
• Enzymes called DNA glycosylases recognize and remove deaminated and modified bases by cleaving the N-glycosyl bond, creating an AP site.
• Another enzyme then repairs the AP site by removing the deoxyribose 5'-phosphate and replacing it with a new nucleotide.

Nucleotide-Excision Repair (NER)

• NER repairs DNA lesions that cause large distortions in the helical structure, such as cyclobutane pyrimidine dimers, 6-4 photoproducts, and base adducts.
• The process involves a multisubunit enzyme (excinuclease) that hydrolyzes two phosphodiester bonds on either side of the lesion, followed by the release of the excised oligonucleotides, gap filling by DNA polymerase, and nick sealing by DNA ligase.

Direct Repair

• Direct repair corrects damage without removing a base or nucleotide.
• Examples include:
• Repair of pyrimidine dimers with photolyase: energy derived from absorbed light is used to reverse the photoreaction that caused the lesion.
• Repair of nucleotides with alkylation damage, such as 𝑶6 -methylguanine and 1-methyladenine.