TY - JOUR
T1 - Abasic site recognition by two apurinic/apyrimidinic endonuclease families in DNA base excision repair
T2 - The 3' ends justify the means
AU - Mol, Clifford D.
AU - Hosfield, David J.
AU - Tainer, John A.
N1 - Funding Information:
This work could not have been possible without the patient and expert collaboration with the laboratories of R.P. Cunningham at the State University of New York at Albany, and S. Mitra at the Sealy Center for Molecular Science at the University of Texas Medical Branch (UTMB) in Galveston, TX. We thank S. S. Parikh and C. D. Putnam for insightful discussions, and a critical reading of the manuscript, as well as the staff and facilities at the Cornell High Energy Synchrotron Source (CHESS) and the Stanford Synchrotron Radiation Laboratory (SSRL), which are supported by the National Science Foundation and Department of Energy, respectively. Work on DNA repair in the Tainer and Cunningham laboratories is supported by the National Institutes of Health grant GM46312, a Special Fellowship from the Leukemia Society of America (to C.D.M) and a Graduate Fellowship from the Skaggs Institute for Research (to D.J.H.).
PY - 2000/8/30
Y1 - 2000/8/30
N2 - 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. (C) 2000 Elsevier Science B.V.
AB - 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. (C) 2000 Elsevier Science B.V.
KW - AP endonucleases
KW - Abasic sites
KW - DNA base excision repair
KW - DNA damage
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U2 - 10.1016/S0921-8777(00)00028-8
DO - 10.1016/S0921-8777(00)00028-8
M3 - Article
C2 - 10946230
AN - SCOPUS:0034734377
SN - 0921-8777
VL - 460
SP - 211
EP - 229
JO - Mutation Research - DNA Repair
JF - Mutation Research - DNA Repair
IS - 3-4
ER -