DNA repair network

DNA repair mechanisms are constituted by a set of complementary, highly organized and finely tuned pathways able to correct various types of DNA damage.
The different pathways appear to have partially overlapping functions. They protect the genome against genotoxic agents and are able to eliminate the majority of the cytotoxic and mutagenic DNA lesion formed to ensure genetic stability.

The repair response following genotoxic insults is regulated through adaptive and coordinated mechanisms that include protein post-translational modification and translocation into the nucleus.

Most of base lesions are removed through Excision/Synthesis Repair mechanisms: Base Excision Repair (BER) and Nucleotide Excision Repair (NER).

Dedicated tools that acknowledge the complexity of DNA Repair are required. LXRepair tests respond to this need.

Schematic representation of the main steps of Excision/Synthesis Repair mechanisms:

Schematic representation of the main steps of Excision/Synthesis Repair mechanisms, LXRepair

Bases Excision Repair

BER is initiated by Glycosylases that recognize and cleave “small” base lesions produced by alkylation, oxidation or deamination of normal bases. The resulting abasic sites (AP sites) are then processed by an AP endonuclease. Bifunctional glycosylases display intrinsic AP lyase activity. The resulting gap is filled by polymerases and ligated.

Each glycosylase exhibits a specific substrate spectrum.

Main substrates and their associated Human Glycosylases/AP endonuclease:
Lesions/paired baseHuman GlycosylaseNature
8oxoG/C hOGG1 bifunctional
A/8oxoG hMYH bifunctional
U/G SMUG, UNG monofunctional
U/A UNG monofunctional
Tg/A hNTH1, NEIL1 bifunctional
Hx/T MPG bifunctional
EthenoA/T MPG bifunctional
AP site (THF)/T APE1 endonuclease


Hx: hypoxanthine;
U: uracil;
Tg: thymine Glycol;
THF: tetrahydrofuran, chemical analog of abasic site (AP site)

Nucleotide Excision Repair

NER removes a variety of DNA damage including helix-distorting lesions like photoproducts and bulky lesion. It participates to the removal of Inter-Strand Crosslinks.

Specific damage sensing factors comprising DDB1, DDB2, and XPC-hHR23B contribute to damage recognition (Global Genome Repair (GGR)). Depending on lesion structure, damage recognition factors and damage recognition factor enhancers differ. Alternatively Transcription-Coupled Repair (TCR) is initiated when RNA polymerase II stalls at a lesion. CSA and CSB are additional factors required for TCR. Transcription factor IIH (TFIIH), is recruited to the damaged site. XPA-RPA verifies whether the NER complex is correctly assembled and XPB and XPD helicases unwind the double-helix. Then a short single-stranded DNA segment that contains the lesion is removed after its incision by the endonucleases XPG and XPF-ERCC1.

DNA polymerases fill in the gap using the complementary sequence as a template. Final ligation is carried out by a DNA Ligase.

Recent reviews on DNA Repair:

Overview of Base Excision Repair Biochemistry,
Kim J and Wilson III DM, Current Mol Pharmacol. 2012 5:3-13

Nucleotide Excision Repair: new tricks with old bricks. Kamileri I, Karakasilioti I and Garinis GA. Trends Genet. 2012 28:566-73.