DNA-(apurinic or apyrimidinic site) lyase

DNA-(apurinic or apyrimidinic site) lyase

DNA-(apurinic or apyrimidinic site) lyase repairing an AP site in DNA.

DNA-(apurinic or apyrimidinic site) lyase, also known as AP lyase or AP endonuclease, is an essential enzyme involved in the repair of DNA damage. It plays a crucial role in the base excision repair (BER) pathway, which is responsible for removing damaged or abnormal bases from DNA.

Function

AP lyase acts specifically on apurinic or apyrimidinic (AP) sites, which are DNA lesions that lack a purine or pyrimidine base due to the spontaneous hydrolysis or enzymatic removal of the damaged base. These sites are highly mutagenic and can lead to DNA strand breaks if left unrepaired.

The main function of AP lyase is to cleave the DNA backbone at the AP site, generating a single-strand break. This enzymatic activity is crucial for the subsequent repair steps in the BER pathway. By creating a nick in the DNA strand, AP lyase allows other repair enzymes to remove the damaged base and replace it with the correct nucleotide.

Mechanism of Action

AP lyase utilizes a metal ion, typically magnesium or zinc, as a cofactor to catalyze the cleavage of the DNA backbone. It recognizes the AP site and binds to the damaged DNA strand. The enzyme then initiates a β-elimination reaction, which results in the cleavage of the phosphodiester bond adjacent to the AP site.

The cleavage reaction generates a 3'-hydroxyl group and a 5'-deoxyribose phosphate (dRP) residue. The 3'-hydroxyl group serves as a primer for the subsequent steps of the BER pathway, while the dRP residue is removed by a separate enzyme called dRPase.

Importance in DNA Repair

The repair of AP sites is crucial for maintaining the integrity of the genome. If left unrepaired, AP sites can lead to mutations, DNA strand breaks, and genomic instability. Additionally, AP sites can block the progression of DNA polymerases during replication, resulting in replication fork stalling and DNA damage accumulation.

AP lyase plays a vital role in the repair of AP sites by initiating the BER pathway. Its ability to cleave the DNA backbone at the AP site allows for the removal and replacement of the damaged base, ensuring the accurate replication and transcription of genetic information.

Clinical Significance

Mutations or deficiencies in AP lyase can have severe consequences for DNA repair and genomic stability. Inherited deficiencies in AP lyase have been associated with increased susceptibility to certain types of cancer, as well as neurodegenerative diseases such as Alzheimer's and Parkinson's.

Furthermore, AP lyase is a target for certain chemotherapeutic agents that aim to selectively kill cancer cells by inhibiting DNA repair mechanisms. By blocking the activity of AP lyase, these drugs can enhance the sensitivity of cancer cells to DNA damage, leading to their selective elimination.

See Also

• Base excision repair
• DNA repair
• DNA polymerase
• DNA damage
• Genomic instability