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Phosphate steering by Flap Endonuclease 1 promotes 5'-flap specificity and incision to prevent genome instability.

Abstract：

:DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via 'phosphate steering', basic residues energetically steer an inverted ss 5'-flap through a gateway over FEN1's active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA)n repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5'-flap specificity and catalysis, preventing genomic instability.

journal_name

Nat Commun

journal_title

Nature communications

authors

Tsutakawa SE,Thompson MJ,Arvai AS,Neil AJ,Shaw SJ,Algasaier SI,Kim JC,Finger LD,Jardine E,Gotham VJB,Sarker AH,Her MZ,Rashid F,Hamdan SM,Mirkin SM,Grasby JA,Tainer JA

doi

10.1038/ncomms15855

subject

Has Abstract

pub_date

2017-06-27 00:00:00

pages

15855

issn

2041-1723

pii

ncomms15855

journal_volume

8

pub_type

杂志文章

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