241:
81:) cleave 3′ to AP sites by a β-lyase mechanism, leaving an unsaturated aldehyde, termed a 3′-(4-hydroxy-5-phospho-2-pentenal) residue, and a 5′-phosphate. Class II AP endonucleases incise DNA 5′ to AP sites by a hydrolytic mechanism, leaving a 3′-hydroxyl and a 5′-deoxyribose phosphate residue. Class III and class IV AP endonucleases also cleave DNA at the phosphate groups 3′ and 5′ to the baseless site, but they generate a 3′-phosphate and a 5′-OH.
125:
22:
117:
266:. Both of these structures possess rings attached to short chains, which appear similar to the deoxyribose sugar ring without a base attached and phosphodiester bond in DNA. Further, both contain many H-bond acceptors which may interact with the H-bond donors in the active site of APE1, causing these inhibitors to stick in the active site and preventing the enzyme from catalyzing other reactions.
253:
274:
Because APE1 performs an essential function in DNA base-excision repair pathway, it has become a target for researchers looking for means to prevent cancer cells from surviving chemotherapy. Not only is APE1 needed in and of itself to create the nick in the DNA backbone so that the enzymes involved
286:
The APE2 3' –5' exonuclease activity has the ability to hydrolyze blunt-ended duplex DNA, partial DNA duplexes with a recessed 3' -terminus or a single nucleotide gap containing heteroduplex DNA. The APE2 3'-phosphodiesterase activity can remove modified 3'-termini, such as 3'-phosphoglycolate as
99:
Human AP Endonuclease 2 (APE2), like most AP endonucleases, is also of class II. The exonuclease activity of APE2 is strongly dependent upon metal ions. However, APE2 was more than 5-fold more active in the presence of manganese than of magnesium ions. The conserved domains involved in catalytic
236:
through a simple acyl substitution mechanism. First, the Asp210 residue in the active site deprotonates a water molecule, which can then perform a nucleophilic attack on the phosphate group located 5´ to the AP site. Next, electrons from one of the oxygen atom in the phosphate group moves down,
92:. APE1 exhibits robust AP-endonuclease activity, which accounts for >95% of the total cellular activity, and APE1 is considered to be the major AP endonuclease in human cells. Human AP endonuclease (APE1), like most AP endonucleases, is of class II and requires an Mg in its
275:
later in the BER pathway can recognize the AP-site, it also has a redox function that helps activate other enzymes involved in DNA repair. As such, knocking down APE1 could lead to tumor cell sensitivity, thus preventing cancer cells from persisting after chemotherapy.
100:
activity are located at the N-terminal part of both APE1 and APE2. In addition, the APE2 protein has a C-terminal extension, which is not present in APE1, but can also be found in homologs of human APE2 such as APN2 proteins of
298:
Molecular graphics images were produced using the UCSF Chimera package from the
Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR-01081).
128:
Hydrogen bonding among key amino acid residues help stabilize active site structure. Moreover, a negatively charged residue (Glu 96) helps hold the Mg2+ also needed to stabilize the AP site in place PDB
283:
APE2 has much weaker AP endonuclease activity than APE1, but its 3'-5' exonuclease activity is strong compared with APE1 and it has a fairly strong 3'-phosphodiesterase activity.
577:
Mark R. Kelley; Meihua Luo; Sarah
Delaphlane; Aihua Jiang; April Reed; Ying He; Melissa Fishel; Rodney L. Nyland II; Richard F. Broch; Xizoxi Qiao; Millie M. Georgiadis (2008).
507:
George W. Teebor; Dina R. Marensein; David M. Wilson III (2004). "Human AP endonuclease (APE1) demonstrates endonucleolytic activity against AP sites in single-stranded DNA".
237:
kicking off one of the other oxygen to create a free 5´ phosphate group on the AP site and a free 3´-OH on the normal nucleotide, both of which are stabilized by the Mg ion.
733:
579:"Role of the Multifunctional DNA Repair and Redox Signaling Protein Ape1/Ref-1 in Cancer and Endothelial Cells: Small-Molecule Inhibition of the Redox Function of Ape1"
320:
Clifford D. Mol; Tahide Izumi; Sankar Mitra; John A. Tainer (2000). "DNA-bound structures and mutants reveal abasic DNA binding by APE1 DNA repair and coordination".
157:
127 span and widen the minor groove, anchoring the DNA for the extreme kinking caused by the interaction between positive residues found in four loops and one
120:
Positive residues on the surface of the APE1 protein (in blue) anchor and bend DNA though interactions with DNA's negative phosphate groups. PDB 1de9.
628:"Differential expression of APE1 and APE2 in germinal centers promotes error-prone repair and A:T mutations during somatic hypermutation"
542:
Mark R. Kelley; Melissa L. Fishel (2007). "The DNA base excision repair protein Ape1/Ref-1 as a
Therapeutic and chemopreventive target".
763:
775:
730:
365:"Analysis of class II (hydrolytic) and class I (beta-lyase) apurinic/apyrimidinic endonucleases with a synthetic DNA substrate"
626:
Stavnezer J, Linehan EK, Thompson MR, Habboub G, Ucher AJ, Kadungure T, Tsuchimoto D, Nakabeppu Y, Schrader CE (2014).
220:
that attacks and cleaves the phosphodiester backbone and probably results in the observed maximal APE1 activity at a
184:
side of the AP site, discriminating against sites that do have bases. The AP site is then further stabilized through
414:
149:
78) contact three consecutive DNA phosphates on the strand opposite the one containing the AP site while
216:) caused through its stabilization through its hydrogen bonding between Asn68 and Asn212, activates the
460:"Human Ape2 protein has a 3'-5' exonuclease activity that acts preferentially on mismatched base pairs"
213:
74:
that have been classified according to their mechanism and site of incision. Class I AP endonucleases (
677:
E.F. Pettersen; T.D. Goddard; C.C. Huang; G.S. Couch; D.M. Greenblat; E.C. Meng; T.E. Ferrin (2004).
75:
96:
in order to carry out its role in base excision repair. The yeast homolog of this enzyme is APN1.
196:
309, and the Mg ion while its orphan base partner is stabilized through hydrogen bonding with
48:
773:
Purification and characterization of an apurinic/apyrimidinic endonuclease from HeLa cells
8:
760:
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364:
772:
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524:
489:
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337:
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200:
270. The phosphate group 3' to the AP site is stabilized through hydrogen bonding to
678:
506:
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516:
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185:
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520:
208:
210 in the active site, which is made more reactive due to the increase in its pK
137:
residues that enable it to react selectively with AP sites. Three APE1 residues (
64:
161:
and the negative phosphate groups found in the phosphodiester backbone of DNA.
56:
676:
555:
290:
APE2 is required for ATR-Chk1 DNA damage response following oxidative stress.
788:
679:"UCSF Chimera - A Visualization System for Exploratory Research and Analysis"
380:
205:
169:
644:
705:
663:
612:
563:
528:
493:
341:
262:
Known inhibitors of APE1 include 7-nitroindole-2-carboxylic acid (NCA) and
71:
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398:
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233:
217:
181:
165:
93:
78:
52:
427:
240:
263:
256:
197:
189:
173:
134:
697:
158:
333:
193:
232:
The APE1 enzyme creates a nick in the phosphodiester backbone at an
164:
This extreme kinking forces the baseless portion of DNA into APE1's
124:
51:
pathway (BER). Its main role in the repair of damaged or mismatched
201:
150:
138:
21:
755:
746:
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154:
142:
60:
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41:
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well as mismatched nucleotides from the 3' primer end of DNA.
116:
457:
252:
45:
411:
221:
458:
Burkovics P, Szukacsov V, Unk I, Haracska L (2006).
412:Gary M. Myles; Aziz Sancar (1989). "DNA Repair".
269:
786:
761:Application in Long Patch Base Excision Repair
188:of the phosphate group 5´ to the AP site with
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602:
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363:Levin, Joshua D; Demple, Bruce (1990).
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405:
111:
25:Ribbon diagram of APE1. PDB = 1de9.
731:Basic Definition of AP endonuclease
13:
583:Antioxidants & Redox Signaling
304:
239:
168:. This active site is bordered by
84:Humans have two AP endonucleases,
55:in DNA is to create a nick in the
14:
806:
724:
180:282, which pack tightly with the
415:Chemical Research in Toxicology
356:
270:APE1 as chemopreventive target
1:
544:Molecular Aspects of Medicine
293:
16:Enzyme involved in DNA repair
632:Proc. Natl. Acad. Sci. U.S.A
521:10.1016/j.dnarep.2004.01.010
227:
7:
70:There are four types of AP
10:
811:
214:acid dissociation constant
67:removes the damaged base.
752:AP endonucleases family 2
743:AP endonucleases family 1
556:10.1016/j.mam.2007.04.005
212:(or the negative log of
44:that is involved in the
645:10.1073/pnas.1405590111
381:10.1093/nar/18.17.5069
369:Nucleic Acids Research
259:
244:
234:abasic (baseless) site
133:APE1 contains several
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121:
26:
595:10.1089/ars.2008.2120
255:
243:
127:
119:
30:Apurinic/apyrimidinic
24:
279:APE2 enzyme activity
49:base excision repair
428:10.1021/tx00010a001
204:177. Meanwhile, an
778:2007-09-29 at the
766:2007-09-29 at the
736:2010-06-20 at the
476:10.1093/nar/gkl259
260:
248:Inhibition of APE1
245:
131:
122:
27:
698:10.1002/jcc.20084
692:(13): 1605–1612.
464:Nucleic Acids Res
328:(6768): 451–456.
112:Structure of APE1
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550:(3–4): 375–395.
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186:hydrogen bonding
59:backbone of the
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780:Wayback Machine
768:Wayback Machine
738:Wayback Machine
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375:(17): 5069–75.
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65:DNA glycosylase
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725:External links
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57:phosphodiester
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102:S. cerevisiae
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72:endonucleases
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66:
63:created when
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47:
43:
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35:
31:
23:
19:
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589:(11): 1–12.
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38:endonuclease
37:
33:
29:
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18:
218:nucleophile
182:hydrophobic
166:active site
94:active site
53:nucleotides
509:DNA Repair
294:References
264:lucanthone
257:Lucanthone
135:amino acid
228:Mechanism
176:280, and
79:4.2.99.18
789:Category
776:Archived
764:Archived
734:Archived
706:15264254
664:24927551
613:18627350
564:17560642
529:15084314
494:16687656
342:10667800
224:of 7.5.
153:128 and
145:74, and
106:S. pombe
795:Enzymes
756:PROSITE
747:PROSITE
714:8747218
655:4078814
604:2587278
485:1459411
436:2519777
399:1698278
350:4373743
159:α-helix
61:AP site
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390:332125
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322:Nature
42:enzyme
40:is an
710:S2CID
682:(PDF)
346:S2CID
172:266,
129:1de9.
702:PMID
660:PMID
609:PMID
560:PMID
525:PMID
490:PMID
432:PMID
395:PMID
338:PMID
141:73,
104:and
90:APE2
88:and
86:APE1
754:in
745:in
694:doi
650:PMC
640:doi
636:111
599:PMC
591:doi
552:doi
517:doi
480:PMC
472:doi
424:doi
385:PMC
377:doi
330:doi
326:403
206:Asp
202:Arg
198:Met
194:His
190:Asn
178:Leu
174:Trp
170:Phe
155:Gly
151:Tyr
147:Lys
143:Ala
139:Arg
46:DNA
791::
708:.
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690:25
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468:34
466:.
462:.
444:^
430:.
418:.
393:.
383:.
373:18
371:.
367:.
344:.
336:.
324:.
306:^
222:pH
108:.
76:EC
36:)
34:AP
716:.
696::
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642::
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593::
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554::
531:.
519::
513:3
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420:2
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379::
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332::
210:a
32:(
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