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Titolo:
SPECIFIC RECOGNITION OF SUBSTRATE-ANALOGS BY THE DNA MISMATCH REPAIR ENZYME MUTY
Autore:
PORELLO SL; WILLIAMS SD; KUHN H; MICHAELS ML; DAVID SS;
Indirizzi:
UNIV UTAH,DEPT CHEM SALT LAKE CITY UT 84112 UNIV CALIF SANTA CRUZ,DEPT CHEM & BIOCHEM SANTA CRUZ CA 95064 AMGEN INC THOUSAND OAKS CA 91320
Titolo Testata:
Journal of the American Chemical Society
fascicolo: 44, volume: 118, anno: 1996,
pagine: 10684 - 10692
SICI:
0002-7863(1996)118:44<10684:SROSBT>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
ESCHERICHIA-COLI MUTY; G-A MISPAIRS; CRYSTAL-STRUCTURE; 8-HYDROXYGUANINE 7,8-DIHYDRO-8-OXOGUANINE; FORMYCIN 5'-PHOSPHATE; CATALYTIC MECHANISM; ENDONUCLEASE-III; AMP NUCLEOSIDASE; MINOR-GROOVE; BASE-PAIRS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
60
Recensione:
Indirizzi per estratti:
Citazione:
S.L. Porello et al., "SPECIFIC RECOGNITION OF SUBSTRATE-ANALOGS BY THE DNA MISMATCH REPAIR ENZYME MUTY", Journal of the American Chemical Society, 118(44), 1996, pp. 10684-10692

Abstract

The DNA repair enzyme MutY plays an important role in the prevention of DNA mutations caused by the oxidatively damaged lesion 7,8-dihydro-8-oxo-2'-deoxyguanosine (OG) by removal of misincorporated adenine residues in OG:A mismatched base pairs using N-glycosylase activity. MutYalso has glycosylase activity toward adenine in the mismatched base-pairs G:A and C:A. We have investigated the interaction of MutY with DNA duplexes containing the 2'-deoxyadenosine (A) analogs 2'-deoxytubercidin (7-deaza-2'-deoxyadenosine, Z) and 2'-deoxyformycin A (F). Both Fand Z should effectively mimic the recognition properties of A but beresistant to the glycosylase activity of MutY, owing to their structural properties. Thus, these derivatives will provide a method for forming a stable MutY-substrate analog complex amenable to structural and biochemical investigation. We find that oligonucleotide duplexes containing OG/G:F and OG/G:Z base-pairs are not substrates for MutY as expected. Using a gel retardation method to measure relevant K-d values, we determined that MutY has an increased association with duplexes containing OG/G:F and OG/G:Z base-pairs over their OG/G:C counterparts. Interestingly, MutY has a higher affinity for the F-containing duplexes than the Z counterparts. Additionally, MutY binds to the OG:F and G:F duplexes with a similar, albeit lower, affinity as the substrate OG:A and G:A duplexes. In footprinting experiments using methidiumpropyl-EDTA-Fe(II), a region of the duplex surrounding the OG:F base-pair is observed which is protected by MutY from hydroxyl radical cleavage. These results provide additional evidence for specific recognition of the OG:F base-pair within the DNA duplex. Furthermore, these results also illustrate the utility of OG:F duplexes for providing information regarding the MutY-mismatched DNA complex which could not be obtained withthe normal OG:A substrate since a footprint on both strands of the duplex could only be observed with the OG:F-containing duplex. These substrate analog duplexes will provide avenues for structural analysis ofthe MutY-mismatched DNA complex and for investigating the properties of the unusual [4Fe-4S] center in MutY.

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Documento generato il 09/08/20 alle ore 23:31:36