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Orlando Scharer
유전체 항상성 연구단
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Structural mechanism of DNA interstrand cross-link unhooking by the bacterial FAN1 nuclease

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dc.contributor.authorHyeonseok Jin-
dc.contributor.authorUpasana Roy-
dc.contributor.authorGwangrog Lee-
dc.contributor.authorOrlando D. Scharer-
dc.contributor.authorYunje Cho-
dc.date.available2019-01-03T05:34:16Z-
dc.date.created2018-06-12-
dc.date.issued2018-04-
dc.identifier.issn0021-9258-
dc.identifier.urihttp://pr.ibs.re.kr/handle/8788114/5286-
dc.description.abstractDNA interstrand cross-links (ICLs) block the progress of the replication and transcription machineries and can weaken chromosomal stability, resulting in various diseases. FANCD2-FANCI-associated nuclease (FAN1) is a conserved structure-specific nuclease that unhooks DNA ICLs independently of the Fanconi anemia pathway. Recent structural studies have proposed two different mechanistic features for ICL unhooking by human FAN1: a specific basic pocket that recognizes the terminal phosphate of a 1-nucleotide (nt) 5 flap or FAN1 dimerization. Herein, we show that despite lacking these features, Pseudomonas aeruginosa FAN1 (PaFAN1) cleaves substrates at approximate to 3-nt intervals and resolves ICLs. Crystal structures of PaFAN1 bound to various DNA substrates revealed that its conserved basic Arg/Lys patch comprising Arg-228 and Lys-260 recognizes phosphate groups near the 5 terminus of a DNA substrate with a 1-nt flap or a nick. Substitution of Lys-260 did not affect PaFAN1's initial endonuclease activity but significantly decreased its subsequent exonuclease activity and ICL unhooking. The Arg/Lys patch also interacted with phosphates at a 3-nt gap, and this interaction could drive movement of the scissile phosphates into the PaFAN1-active site. In human FAN1, the ICL-resolving activity was not affected by individual disruption of the Arg/Lys patch or basic pocket. However, simultaneous substitution of both FAN1 regions significantly reduced its ICL-resolving activity, suggesting that these two basic regions play a complementary role in ICL repair. On the basis of these findings, we propose a conserved role for two basic regions in FAN1 to guide ICL unhooking and to maintain genomic stability-
dc.languageENG-
dc.publisherAMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC-
dc.titleStructural mechanism of DNA interstrand cross-link unhooking by the bacterial FAN1 nuclease-
dc.typeArticle-
dc.type.rimsA-
dc.identifier.wosid000431108600021-
dc.identifier.scopusid2-s2.0-85046031862-
dc.contributor.affiliatedAuthorOrlando D. Scharer-
dc.identifier.bibliographicCitationJOURNAL OF BIOLOGICAL CHEMISTRY, v.293, no.17, pp.6482 - 6496-
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > Journal Papers (저널논문)
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2018_J. Biol. Chem._Structural mechanism of DNA interstrand cross-link unhooking by the bacterial FAN1 nuclease_Scharer, OD_2소속,사사.pdfDownload

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