Genetics · MU Sofia

5. Mechanisms of DNA repair: direct repair; excision repair; single-strand break repair (SSBR); double-strand break repair (DSBR).

Covers the main ways cells repair damaged DNA, starting with direct reversal of damage by enzymes such as photolyase and MGMT, then excision repair in its base and nucleotide forms. It moves on to single-strand break repair with PARP and XRCC1, and ends with double-strand break repair through homologous recombination and non-homologous end joining. Clinical links such as xeroderma pigmentosum, BRCA mutations and SCID are noted, along with a closing key-points summary.

Inside: 8 sections · 4 labelled pictures · 15 flashcards · 4 min

Topic 5 of 65 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 8 sections, about 540 words (4 min of reading), with 15 flashcards.

In this note

  1. Mechanisms of DNA Repair
  2. I. Introduction
  3. II. Direct Repair (Reversal of Damage)
  4. III. Excision Repair
  5. IV. Single-Strand Break Repair (SSBR)
  6. V. Double-Strand Break Repair (DSBR)
  7. VI. Clinical Importance of DNA Repair
  8. VII. Key Points

I. Introduction

DNA is constantly exposed to damage from internal sources (replication errors, reactive oxygen species, spontaneous chemical changes) and external sources (UV light, ionizing radiation, chemicals). If left unrepaired, such damage leads to mutations, cancer, or cell death. Cells therefore have multiple, overlapping repair mechanisms to maintain genomic stability.

II. Direct Repair (Reversal of Damage)

  • Definition: Directly restores the altered base to its original form without removing it.
  • Mechanisms:
  1. 1. Photoreactivation (in bacteria, not humans)
  • Enzyme: DNA photolyase.
  • Repairs UV-induced thymine dimers by using visible light energy.
  1. 2. Alkyltransferases
  • Example: O6-methylguanine-DNA methyltransferase (MGMT).
  • Removes alkyl groups directly from guanine bases.
  • One-time use enzyme → sacrificed after repair.
  1. 3. Dealkylases and demethylases
  • Reverse abnormal methylation or alkylation.

Clinical note: Loss of MGMT activity → increased susceptibility to mutagenesis and certain cancers.

III. Excision Repair

Excision mechanisms remove damaged bases/nucleotides and resynthesize the DNA.

1. Base Excision Repair (BER)

  • Repairs small, non-helix-distorting lesions (e.g., uracil misincorporation, oxidized bases, alkylated bases).
  • Steps:
  1. 1. DNA glycosylase recognizes damaged base and removes it → creates AP (apurinic/apyrimidinic) site.
  2. 2. AP endonuclease cleaves phosphodiester bond at AP site.
  3. 3. DNA polymerase β inserts correct nucleotide.
  4. 4. DNA ligase seals nick.

2. Nucleotide Excision Repair (NER)

  • Repairs bulky, helix-distorting lesions: thymine dimers (UV damage), chemical adducts.
  • Steps:
  1. 1. Damage recognition complex identifies lesion.
  2. 2. Helicase unwinds DNA around lesion.
  3. 3. Excision endonucleases cut ~24–32 bp segment containing lesion.
  4. 4. DNA polymerase δ/ε fills gap.
  5. 5. DNA ligase seals strand.

Clinical correlation:

  • Xeroderma pigmentosum = defect in NER → extreme UV sensitivity, skin cancers.

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