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Importance of homo-dimerization of Fanconi-associated nuclease 1 in DNA flap cleavage.

Authors
  • Rao, Timsi1
  • Longerich, Simonne1
  • Zhao, Weixing1
  • Aihara, Hideki2
  • Sung, Patrick3
  • Xiong, Yong4
  • 1 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA.
  • 2 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA.
  • 3 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA. Electronic address: [email protected]
  • 4 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA. Electronic address: [email protected]
Type
Published Article
Journal
DNA repair
Publication Date
Apr 01, 2018
Volume
64
Pages
53–58
Identifiers
DOI: 10.1016/j.dnarep.2018.02.007
PMID: 29518739
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Fanconi-associated nuclease 1 (FAN1) removes interstrand DNA crosslinks (ICLs) through its DNA flap endonuclease and exonuclease activities. Crystal structures of human and bacterial FAN1 bound to a DNA flap have been solved. The Pseudomonas aeruginosa bacterial FAN1 and human FAN1 (hFAN1) missing a flexible loop are monomeric, while intact hFAN1 is homo-dimeric in structure. Importantly, the monomeric and dimeric forms of FAN1 exhibit very different DNA binding modes. Here, we interrogate the functional differences between monomeric and dimeric forms of FAN1 and provide an explanation for the discrepancy in oligomeric state between the two hFAN1 structures. Specifically, we show that the flexible loop in question is needed for hFAN1 dimerization. While monomeric and dimeric bacterial or human FAN1 proteins cleave a short 5' flap strand with similar efficiency, optimal cleavage of a long 5' flap strand is contingent upon protein dimerization. Our study therefore furnishes biochemical evidence for a role of hFAN1 homodimerization in biological processes that involve 5' DNA Flap cleavage. Copyright © 2018 Elsevier B.V. All rights reserved.

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