The crystal structure of the human DNA repair endonuclease HAP1 suggests the recognition of extra-helical deoxyribose at DNA abasic sites.
The structure of the major human apurinic/ apyrimidinic endonuclease (HAP1) has been solved at 2.2 A resolution. The enzyme consists of two symmetrically related domains of similar topology and has significant structural similarity to both bovine DNase I and its Escherichia coli homologue exonuclease III (EXOIII). A structural comparison of these enzymes reveals three loop regions specific to HAP1 and EXOIII. These loop regions apparently act in DNA abasic site (AP) recognition and cleavage since DNase I, which lacks these loops, correspondingly lacks AP site specificity. The HAP1 structure furthermore suggests a mechanism for AP site binding which involves the recognition of the deoxyribose moiety in an extrahelical conformation, rather than a 'flipped-out' base opposite the AP site.
Gorman
M A
MA
Protein Structure Laboratory, Imperial Cancer Research Fund, London, UK.
Morera
S
S
Rothwell
D G
DG
de La Fortelle
E
E
Mol
C D
CD
Tainer
J A
JA
Hickson
I D
ID
Freemont
P S
PS
D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D019757:Carbon-Oxygen Lyases; D002417:Cattle; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D003850:Deoxyribonuclease I / Q000737:chemistry; D004720:Endonucleases / Q000737:chemistry*; D004926:Escherichia coli / Q000737:chemistry; D005090:Exodeoxyribonucleases / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry*; D010084:Oxidation-Reduction; D011485:Protein Binding; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D001426:Bacterial Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D004247:DNA; D004720:Endonucleases; D005090:Exodeoxyribonucleases; C020133:exodeoxyribonuclease III; D003850:Deoxyribonuclease I; D019757:Carbon-Oxygen Lyases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase