U01.01.009 DNA repair

Mechanism:
- Specific endonucleases release the oligonucleotides containing damaged bases.
- DNA polymerase fills the gap.
- DNA ligase reseals the gap.
Characteristics:
- Repairs bulky helix-distorting lesions.
- Occurs in the G1 phase of the cell cycle.
Clinical Correlation:
- Defective in xeroderma pigmentosum (inability to repair DNA pyrimidine dimers caused by UV exposure).
- Findings: Dry skin, extreme light sensitivity, skin cancer.

Mechanism:
- Base-specific glycosylase removes the altered base and creates an AP site (apurinic/apyrimidinic).
- AP-endonuclease cleaves the 5′ end.
- AP-lyase cleaves the 3′ end.
- DNA polymerase-β fills the gap.
- DNA ligase seals it.
Characteristics:
- Occurs throughout the cell cycle.
- Important in the repair of spontaneous/toxic deamination.
Mnemonic: “GEL Please” (Glycosylase, Endonuclease, Lyase, Polymerase, Ligase).

Mechanism:
- Mismatched nucleotides in the newly synthesized (unmethylated) strand are removed.
- Gap is filled and resealed.
Characteristics:
- Occurs predominantly in S phase of the cell cycle.
Clinical Correlation:
- Defective in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]).

Mechanism:
- Brings together two ends of DNA fragments to repair double-stranded breaks.
- No requirement for homology.
- Some DNA may be lost in the process.
Clinical Correlation:
- Defective in ataxia-telangiectasia.

Mechanism:
- Requires two homologous DNA duplexes.
- A strand from damaged dsDNA is repaired using a complementary strand from intact homologous dsDNA as a template.
- Restores duplexes accurately without loss of nucleotides.
Clinical Correlation:
- Defective in breast/ovarian cancers with BRCA1 mutation.
- Defective in Fanconi anemia.

NER: Repairs bulky lesions; defective in xeroderma pigmentosum.
BER: Repairs spontaneous/toxic deamination; occurs throughout the cell cycle.
MMR: Predominantly in the S phase; defective in Lynch syndrome.
NHEJ: No homology required; defective in ataxia-telangiectasia.
HR: Requires homologous DNA; accurate repair; defective in BRCA1-related cancers and Fanconi anemia.

The phase of Cell Cycle	Phase of Cell Cycle	Key Enzymes Involved	Clinical Correlation
Nucleotide Excision Repair (NER)	G1 phase	Endonucleases, DNA polymerase, DNA ligase	Xeroderma pigmentosum
Base Excision Repair (BER)	Throughout cycle	Glycosylase, AP-endonuclease, AP-lyase, DNA polymerase-β, DNA ligase	Repair of spontaneous/toxic deamination
Mismatch Repair (MMR)	S phase	Mismatch repair proteins	Lynch syndrome (HNPCC)
Nonhomologous End Joining (NHEJ)	Throughout cycle	Various enzymes	Ataxia-telangiectasia
Homologous Recombination (HR)	S and G2 phases	Recombinase, various other proteins	BRCA1-related cancers, Fanconi anemia

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