DNA repair - BER, NER, MMR, direct repair of modified bases.

DNA repair is a vital set of processes by which cells identify and correct damage to the DNA molecules that encode their genomes. Every day, cells are exposed to endogenous and exogenous agents (e.g., reactive oxygen species, UV light, radiation) that damage DNA. Without repair, this damage can lead to mutations, genomic instability, cancer, or cell death.

To maintain genomic integrity, cells employ various repair pathways, including **base excision repair (BER)**, **nucleotide excision repair (NER)**, **mismatch repair (MMR)**, and **direct reversal of base damage**.

Base excision repair (BER)

BER repairs small, non-helix-distorting base lesions caused by oxidation, alkylation, or deamination.

• **Steps:**

1. A **DNA glycosylase** recognizes and removes the damaged base, creating an abasic (AP) site.
2. **AP endonuclease (APE1)** cuts the DNA backbone at the AP site.
3. **DNA polymerase β** inserts the correct base.
4. **DNA ligase III** (or ligase I) seals the nick.

• **Examples of damage repaired:**
  • Uracil in DNA (from cytosine deamination)
  • 8-oxoguanine (oxidative damage)
  • Single-strand breaks

• Base excision repair en.svg

  Base excision repair (BER) mechanism

Nucleotide excision repair (NER)

NER removes bulky, helix-distorting lesions such as thymine dimers or chemical adducts.

• **Global genomic NER** – Scans the entire genome for distortions.
• **Transcription-coupled NER** – Targets lesions on actively transcribed genes.

• **Steps:**

1. DNA damage is recognized by sensor proteins (e.g., XPC-RAD23B).
2. Local DNA unwinding occurs via **TFIIH helicase complex**.
3. Dual incision removes a ~25–30 nucleotide-long fragment.
4. **DNA polymerase δ/ε** fills the gap.
5. **DNA ligase I** seals the DNA.

• **Diseases linked to defective NER:**
  • Xeroderma pigmentosum – extreme UV sensitivity and skin cancer risk.

• Nucleotide excision repair.png

  NER pathway repairing UV-induced thymine dimers

Mismatch repair (MMR)

MMR corrects errors that escape proofreading during DNA replication, such as **base–base mismatches** or **insertion/deletion loops**.

• **Steps:**

1. Mismatch is recognized by **MutSα (MSH2-MSH6)** or **MutSβ (MSH2-MSH3)**.
2. **MutLα (MLH1-PMS2)** is recruited and coordinates downstream steps.
3. Exonuclease 1 removes the segment of the newly synthesized strand.
4. DNA polymerase fills the gap, and DNA ligase seals it.

• **Clinical relevance:**
  • Defects in MMR genes (e.g., **MLH1, MSH2**) cause **Lynch syndrome** (hereditary nonpolyposis colorectal cancer, HNPCC).

Direct repair of modified bases

This type of repair directly reverses specific chemical modifications without removing the base or nucleotide.

1. Photoreactivation (in some organisms)

• Enzyme: **Photolyase**
• Function: Repairs UV-induced **thymine dimers** using visible light.
• Not present in placental mammals, including humans.

2. Methylation damage reversal

• Enzyme: **MGMT (O⁶-methylguanine-DNA methyltransferase)**
• Function: Transfers methyl group from O⁶-methylguanine to itself, restoring guanine.

• Note: MGMT is **suicidal** – the enzyme is inactivated after a single reaction.

Summary table

Repair type	Target lesion	Key enzymes	Notes
Base excision repair (BER)	Oxidized/alkylated bases	DNA glycosylase, APE1	Small, non-bulky lesions
Nucleotide excision repair (NER)	Thymine dimers, bulky adducts	XPC, TFIIH, DNA pol δ/ε	Removes ~30 nt fragment
Mismatch repair (MMR)	Replication errors (mismatches, loops)	MSH2, MLH1, PMS2	Post-replication repair
Direct repair	Methylated bases	MGMT	No removal of bases

Clinical relevance

• Cancer – Defects in MMR and NER pathways are associated with inherited and sporadic cancers.
• Aging – Accumulation of DNA damage contributes to aging.
• Neurodegeneration – Impaired repair is linked to diseases like ataxia-telangiectasia and Alzheimer’s.
• Chemotherapy resistance – High MGMT activity reduces efficacy of alkylating agents like temozolomide.

References

Related articles

• DNA damage
• DNA polymerase
• Nucleotide excision repair
• Mismatch repair
• DNA replication
• Lynch syndrome
• Xeroderma pigmentosum

Literature

• ALBERTS, Bruce. Molecular Biology of the Cell. 6. edition. New York : Garland Science, 2015. 295–310 pp. ISBN 978-0-8153-3218-3.