title: Abasic site recognition by two apurinic/apyrimidinic endonuclease families in DNA base excision repair: the 3' ends justify the means.
abstract: DNA damage occurs unceasingly in all cells. Spontaneous DNA base loss, as well as the removal of damaged DNA bases by specific enzymes targeted to distinct base lesions, creates non-coding and lethal apurinic/apyrimidinic (AP) sites. AP sites are the central intermediate in DNA base excision repair (BER) and must be processed by 5' AP endonucleases. These pivotal enzymes detect, recognize, and cleave the DNA phosphodiester backbone 5' of, AP sites to create a free 3'-OH end for DNA polymerase repair synthesis. In humans, AP sites are processed by APE1, whereas in yeast the primary AP endonuclease is termed APN1, and these enzymes are the major constitutively expressed AP endonucleases in these organisms and are homologous to the Escherichia coli enzymes Exonuclease III (Exo III) and Endonuclease IV (Endo IV), respectively. These enzymes represent both of the conserved 5' AP endonuclease enzyme families that exist in biology. Crystal structures of APE1 and Endo IV, both bound to AP site-containing DNA reveal how abasic sites are recognized and the DNA phosphodiester backbone cleaved by these two structurally unrelated enzymes with distinct chemical mechanisms. Both enzymes orient the AP-DNA via positively charged complementary surfaces and insert loops into the DNA base stack, bending and kinking the DNA to promote flipping of the AP site into a sequestered enzyme pocket that excludes undamaged nucleotides. Each enzyme-DNA complex exhibits distinctly different DNA conformations, which may impact upon the biological functions of each enzyme within BER signal-transduction pathways.
authors.affiliation: Department of Molecular Biology, and Skaggs Institute for Chemical Biology, The Scripps Research Institute, MB4, 10550 North Torrey Pines Road, La Jolla, CA 92037-1027, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Mol
authors.forename: D J
authors.initials: DJ
authors.lastname: Hosfield
authors.forename: J A
authors.initials: JA
authors.lastname: Tainer
mesh_terms: D001080:Apurinic Acid / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D019757:Carbon-Oxygen Lyases / Q000737:chemistry* / Q000502:physiology; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D043223:Deoxyribonuclease IV (Phage T4-Induced); D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins; D005090:Exodeoxyribonucleases / Q000737:chemistry / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011119:Polynucleotides / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D029968:Escherichia coli Proteins; D011119:Polynucleotides; C001790:apyrimidinic acid; D001080:Apurinic Acid; D005090:Exodeoxyribonucleases; C020133:exodeoxyribonuclease III; D043223:Deoxyribonuclease IV (Phage T4-Induced); C468972:endonuclease IV, E coli; D019757:Carbon-Oxygen Lyases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase