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

被引：233

作者：

Tsutakawa, Susan E. ^{[2
]}

Classen, Scott ^{[3
]}

Chapados, Brian R. ^{[4
,5
]}

Arvai, Andrew S. ^{[4
,5
]}

Finger, L. David ^{[2
,6
,7
]}

Guenther, Grant ^{[4
,5
]}

Tomlinson, Christopher G. ^{[1
]}

Thompson, Peter ^{[1
]}

Sarker, Altaf H. ^{[2
]}

Shen, Binghui ^{[6
,7
,8
]}

Cooper, Priscilla K. ^{[2
]}

Grasby, Jane A. ^{[1
]}

Tainer, John A. ^{[2
,4
,5
]}

机构：

[1] Univ Sheffield, Dept Chem, Ctr Chem Biol, Krebs Inst, Sheffield S3 7HF, S Yorkshire, England

[2] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA

[3] Scripps Res Inst, Phys Biosci Div, La Jolla, CA 92037 USA

[4] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA

[5] Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[6] City Hope Natl Med Ctr, Div Radiat Biol, Duarte, CA 91010 USA

[7] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA

[8] Zhejiang Univ, Coll Life Sci, Hangzhou 310058, Zhejiang, Peoples R China

来源：

CELL | 2011年 / 145卷 / 02期

基金：

英国生物技术与生命科学研究理事会;

关键词：

NUCLEOTIDE EXCISION-REPAIR; SACCHAROMYCES-CEREVISIAE; SUBSTRATE-SPECIFICITY; POLYMERASE-BETA; 3'-FLAP POCKET; BINDING; REPLICATION; EXONUCLEASE; CATALYSIS; PCNA;

D O I：

10.1016/j.cell.2011.03.004

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 degrees 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.

引用

页码：198 / 211

页数：14

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