FAN1 activity on asymmetric repair intermediates is mediated by an atypical monomeric virus-type replication-repair nuclease domain

Simon Pennell; Anne-Cécile Déclais; Jiejin Li; Lesley F Haire; Wioletta Berg; José W Saldanha; Ian A Taylor; John Rouse; David M J Lilley; Stephen J Smerdon

doi:10.1016/j.celrep.2014.06.001

FAN1 activity on asymmetric repair intermediates is mediated by an atypical monomeric virus-type replication-repair nuclease domain

Simon Pennell, Anne-Cécile Déclais, Jiejin Li, Lesley F Haire, Wioletta Berg, José W Saldanha, Ian A Taylor, John Rouse, David M J Lilley, Stephen J Smerdon

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

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Abstract

FAN1 is a structure-selective DNA repair nuclease with 5' flap endonuclease activity, involved in the repair of interstrand DNA crosslinks. It is the only eukaryotic protein with a virus-type replication-repair nuclease ("VRR-Nuc") "module" that commonly occurs as a standalone domain in many bacteria and viruses. Crystal structures of three representatives show that they structurally resemble Holliday junction resolvases (HJRs), are dimeric in solution, and are able to cleave symmetric four-way junctions. In contrast, FAN1 orthologs are monomeric and cleave 5' flap structures in vitro, but not Holliday junctions. Modeling of the VRR-Nuc domain of FAN1 reveals that it has an insertion, which packs against the dimerization interface observed in the structures of the viral/bacterial VRR-Nuc proteins. We propose that these additional structural elements in FAN1 prevent dimerization and bias specificity toward flap structures.

Original language	English
Pages (from-to)	84-93
Number of pages	10
Journal	Cell Reports
Volume	8
Issue number	1
Early online date	26 Jun 2014
DOIs	https://doi.org/10.1016/j.celrep.2014.06.001
Publication status	Published - 10 Jul 2014

Bibliographical note

Keywords

Amino Acid Sequence
Animals
Bacterial Proteins/chemistry
DNA Repair
DNA, Cruciform/metabolism
Endodeoxyribonucleases/chemistry
Exodeoxyribonucleases/chemistry
Holliday Junction Resolvases/chemistry
Humans
Mice
Molecular Sequence Data
Protein Binding
Protein Multimerization
Protein Structure, Tertiary
Pseudomonas aeruginosa/enzymology

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Cite this

@article{0cd0eba0e9d24a85ab31d3b33c7a40f3,

title = "FAN1 activity on asymmetric repair intermediates is mediated by an atypical monomeric virus-type replication-repair nuclease domain",

abstract = "FAN1 is a structure-selective DNA repair nuclease with 5' flap endonuclease activity, involved in the repair of interstrand DNA crosslinks. It is the only eukaryotic protein with a virus-type replication-repair nuclease ({"}VRR-Nuc{"}) {"}module{"} that commonly occurs as a standalone domain in many bacteria and viruses. Crystal structures of three representatives show that they structurally resemble Holliday junction resolvases (HJRs), are dimeric in solution, and are able to cleave symmetric four-way junctions. In contrast, FAN1 orthologs are monomeric and cleave 5' flap structures in vitro, but not Holliday junctions. Modeling of the VRR-Nuc domain of FAN1 reveals that it has an insertion, which packs against the dimerization interface observed in the structures of the viral/bacterial VRR-Nuc proteins. We propose that these additional structural elements in FAN1 prevent dimerization and bias specificity toward flap structures.",

keywords = "Amino Acid Sequence, Animals, Bacterial Proteins/chemistry, DNA Repair, DNA, Cruciform/metabolism, Endodeoxyribonucleases/chemistry, Exodeoxyribonucleases/chemistry, Holliday Junction Resolvases/chemistry, Humans, Mice, Molecular Sequence Data, Protein Binding, Protein Multimerization, Protein Structure, Tertiary, Pseudomonas aeruginosa/enzymology",

author = "Simon Pennell and Anne-C{\'e}cile D{\'e}clais and Jiejin Li and Haire, {Lesley F} and Wioletta Berg and Saldanha, {Jos{\'e} W} and Taylor, {Ian A} and John Rouse and Lilley, {David M J} and Smerdon, {Stephen J}",

note = "Copyright {\textcopyright} 2014 The Authors. ",

year = "2014",

month = jul,

day = "10",

doi = "10.1016/j.celrep.2014.06.001",

language = "English",

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pages = "84--93",

journal = "Cell Reports",

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T1 - FAN1 activity on asymmetric repair intermediates is mediated by an atypical monomeric virus-type replication-repair nuclease domain

AU - Pennell, Simon

AU - Déclais, Anne-Cécile

AU - Li, Jiejin

AU - Haire, Lesley F

AU - Berg, Wioletta

AU - Saldanha, José W

AU - Taylor, Ian A

AU - Rouse, John

AU - Lilley, David M J

AU - Smerdon, Stephen J

PY - 2014/7/10

Y1 - 2014/7/10

N2 - FAN1 is a structure-selective DNA repair nuclease with 5' flap endonuclease activity, involved in the repair of interstrand DNA crosslinks. It is the only eukaryotic protein with a virus-type replication-repair nuclease ("VRR-Nuc") "module" that commonly occurs as a standalone domain in many bacteria and viruses. Crystal structures of three representatives show that they structurally resemble Holliday junction resolvases (HJRs), are dimeric in solution, and are able to cleave symmetric four-way junctions. In contrast, FAN1 orthologs are monomeric and cleave 5' flap structures in vitro, but not Holliday junctions. Modeling of the VRR-Nuc domain of FAN1 reveals that it has an insertion, which packs against the dimerization interface observed in the structures of the viral/bacterial VRR-Nuc proteins. We propose that these additional structural elements in FAN1 prevent dimerization and bias specificity toward flap structures.

AB - FAN1 is a structure-selective DNA repair nuclease with 5' flap endonuclease activity, involved in the repair of interstrand DNA crosslinks. It is the only eukaryotic protein with a virus-type replication-repair nuclease ("VRR-Nuc") "module" that commonly occurs as a standalone domain in many bacteria and viruses. Crystal structures of three representatives show that they structurally resemble Holliday junction resolvases (HJRs), are dimeric in solution, and are able to cleave symmetric four-way junctions. In contrast, FAN1 orthologs are monomeric and cleave 5' flap structures in vitro, but not Holliday junctions. Modeling of the VRR-Nuc domain of FAN1 reveals that it has an insertion, which packs against the dimerization interface observed in the structures of the viral/bacterial VRR-Nuc proteins. We propose that these additional structural elements in FAN1 prevent dimerization and bias specificity toward flap structures.

KW - Amino Acid Sequence

KW - Animals

KW - Bacterial Proteins/chemistry

KW - DNA Repair

KW - DNA, Cruciform/metabolism

KW - Endodeoxyribonucleases/chemistry

KW - Exodeoxyribonucleases/chemistry

KW - Holliday Junction Resolvases/chemistry

KW - Humans

KW - Mice

KW - Molecular Sequence Data

KW - Protein Binding

KW - Protein Multimerization

KW - Protein Structure, Tertiary

KW - Pseudomonas aeruginosa/enzymology

U2 - 10.1016/j.celrep.2014.06.001

DO - 10.1016/j.celrep.2014.06.001

M3 - Article

C2 - 24981866

SN - 2211-1247

VL - 8

SP - 84

EP - 93

JO - Cell Reports

JF - Cell Reports

IS - 1

ER -

FAN1 activity on asymmetric repair intermediates is mediated by an atypical monomeric virus-type replication-repair nuclease domain

Abstract

Bibliographical note

Keywords

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