AP endonuclease

AP endonuclease

An AP endonuclease is an enzyme that cuts a strand of DNA on the 5'-side of an AP (apurinic/apyrimidinic) site, as the first step in DNA base excision repair (BER).

AP endonucleases are divided into two families based on their homology to the ancestral bacterial AP endonucleaes endonuclease IV and exonuclease III. [Aravind, L., Walker, D.R. & Koonin, E.V. Conserved domains in DNA repair proteins andevolution of repair systems. Nucleic Acids Res. 27, 1223–1242 (1999).] Many eukaryotes have members of both families, including the yeast Saccharomyces cerevisiae, in which Apn1 is the EndoIV homolog and Apn2 is related to ExoIII. In humans, only a single AP endonuclease, APE1, has been identified. [Demple, B., Herman, T. & Chen, D.S. Cloning and expression of APE, the cDNAencoding the major human apurinic endonuclease: definition of a family of DNA repairenzymes. Proc. Natl. Acad. Sci. USA 88, 11450–11454 (1991).] It is a member of the ExoIII family.

Biochemical activities

Besides incising AP sites, the AP endonucleases also possess 3'-5' exonuclease activity and 3' phosphodiesterase activity. [Demple, B., Johnson, A. & Fung, D. Exonuclease III and endonuclease IV remove 3' blocks from DNA synthesis primers in H2O2-damaged Escherichia coli. Proc. Natl. Acad. Sci. USA 83, 7731–7735 (1986).] These activities are thought to be involved in trimming damaged ends from single-strand breaks in DNA. The ExoIII family requires Mg2+ for activity, whereasthe EndoIV family does not.

Mutant phenotypes

In yeast, both Apn1 and Apn2 must be knocked out to produce a phenotype. The double mutant is sensitive to DNA damaging agents that cause AP sites or single-strand breaks, such as methyl methanesulfonate and hydrogen peroxide. Human cells lacking APE1 are inviable, highlighting the importance of the enzyme in repairing spontaneous DNA damage. [Izumi T, Brown DB, Naidu CV, Bhakat KK, Macinnes MA, Saito H, Chen DJ, Mitra S. Two essential but distinct functions of the mammalian abasic endonuclease. Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5739-43. Epub 2005 Apr 11.]

Role in base excision repair

First DNA glycosylases recognize and excise the damaged bases from the sugar phosphate backbone of the DNA. They do this by cleaving the N-glycosydic bond between the target base and deoxyribose. What is left is an abasic site (or AP, apurinic/apyrimidinic). The group of enzymes called AP-endonucleases recognize the abasic site and make an incision at the 5' or 3' phosphodiester of the AP site which generates a nucleotide gap. It is then filled by polymerization (DNA polymerase I) and ligation (DNA ligase) of the new nucleotide to the existing DNA sequence. Endonucleases, in general, are sometimes referred to as "molecular scissors" because they "cut" a strand of DNA.

External links

* [http://www.biochem.northwestern.edu/holmgren/Glossary/Definitions/Def-A/AP_endonuclease.html Basic Definition]
* [http://www.jbc.org/cgi/content/abstract/277/44/41715 Application in Long Patch Base Excision Repair]
* [http://www.jbc.org/cgi/content/abstract/256/7/3405 Purification and characterization of an apurinic/apyrimidinic endonuclease from HeLa cells]

References


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