Human Flap Endonuclease Structures, DNA Double-Base Flipping, and a Unified Understanding of the FEN1 Superfamily | Zendy

Susan E. Tsutakawa | Zendy; Scott Classen | Zendy; B.R. Chapados | Zendy; A.S. Arvai | Zendy; L. David Finger | Zendy; Grant Guenther | Zendy; Christopher G. Tomlinson | Zendy; Peter Thompson | Zendy; Altaf H. Sarker | Zendy; Binghui Shen | Zendy; Priscilla K. Cooper | Zendy; Jane A. Grasby | Zendy; John A. Tainer | Zendy

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Human Flap Endonuclease Structures, DNA Double-Base Flipping, and a Unified Understanding of the FEN1 Superfamily

Author(s) -

Susan E. Tsutakawa,

Scott Classen,

B.R. Chapados,

A.S. Arvai,

L. David Finger,

Grant Guenther,

Christopher G. Tomlinson,

Peter Thompson,

Altaf H. Sarker,

Binghui Shen,

Priscilla K. Cooper,

Jane A. Grasby,

John A. Tainer

Publication year - 2011

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2011.03.004

Subject(s) - biology , nuclease , dna , holliday junction , homologous recombination , dna repair , replication protein a , oligonucleotide , base pair , endonuclease , dna footprinting , dna replication , homology directed repair , nucleotide excision repair , microbiology and biotechnology , genetics , dna binding protein , gene , transcription factor

Flap endonuclease (FEN1), essential for DNA replication and repair, removes RNA and DNA 5' flaps. FEN1 5' nuclease superfamily members acting in nucleotide excision repair (XPG), mismatch repair (EXO1), and homologous recombination (GEN1) paradoxically incise structurally distinct bubbles, ends, or Holliday junctions, respectively. Here, structural and functional analyses of human FEN1:DNA complexes show structure-specific, sequence-independent recognition for nicked dsDNA bent 100° with unpaired 3' and 5' flaps. Above the active site, a helical cap over a gateway formed by two helices enforces ssDNA threading and specificity for free 5' ends. Crystallographic analyses of product and substrate complexes reveal that dsDNA binding and bending, the ssDNA gateway, and double-base unpairing flanking the scissile phosphate control precise flap incision by the two-metal-ion active site. Superfamily conserved motifs bind and open dsDNA; direct the target region into the helical gateway, permitting only nonbase-paired oligonucleotides active site access; and support a unified understanding of superfamily substrate specificity.

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