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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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Title
Structural mechanism of DNA interstrand cross-link unhooking by the bacterial FAN1 nuclease
Author(s)
Hyeonseok Jin; Upasana Roy; Gwangrog Lee; Orlando D. Scharer; Yunje Cho
Publication Date
2018-04
Journal
JOURNAL OF BIOLOGICAL CHEMISTRY, v.293, no.17, pp.6482 - 6496
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Abstract
DNA 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
URI
http://pr.ibs.re.kr/handle/8788114/5286
ISSN
0021-9258
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > Journal Papers (저널논문)
Files in This Item:
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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