Sequential and Multistep Substrate Interrogation Provides the Scaffold for Specificity in Human Flap Endonuclease 1

Mohamed Abdelmaboud Sobhy, Luay Joudeh, Xiaojuan Huang, Masateru Takahashi, Samir Hamdan

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Human flap endonuclease 1 (FEN1), one of the structure-specific 5' nucleases, is integral in replication, repair, and recombination of cellular DNA. The 5' nucleases share significant unifying features yet cleave diverse substrates at similar positions relative to 5' end junctions. Using single-molecule Förster resonance energy transfer, we find a multistep mechanism that verifies all substrate features before inducing the intermediary-DNA bending step that is believed to unify 5' nuclease mechanisms. This is achieved by coordinating threading of the 5' flap of a nick junction into the conserved capped-helical gateway, overseeing the active site, and bending by binding at the base of the junction. We propose that this sequential and multistep substrate recognition process allows different 5' nucleases to recognize different substrates and restrict the induction of DNA bending to the last common step. Such mechanisms would also ensure the protection ofDNA junctions from nonspecific bending and cleavage. 2013 The Authors.
Original languageEnglish (US)
Pages (from-to)1785-1794
Number of pages10
JournalCell Reports
Volume3
Issue number6
DOIs
StatePublished - Jun 6 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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