FAN1 Activity on Asymmetric Repair Intermediates Is Mediated by an Atypical Monomeric Virus-type Replication-Repair Nuclease Domain

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 bacteri...

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Published in:	Cell reports (Cambridge) Vol. 8; no. 1; pp. 84 - 93
Main Authors:	Pennell, Simon, Déclais, Anne-Cécile, Li, Jiejin, Haire, Lesley F., Berg, Wioletta, Saldanha, José W., Taylor, Ian A., Rouse, John, Lilley, David M.J., Smerdon, Stephen J.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 10-07-2014 Cell Press Elsevier
Subjects:	Amino Acid Sequence Animals Bacterial Proteins - chemistry Bacterial Proteins - metabolism DNA Repair DNA, Cruciform - metabolism Endodeoxyribonucleases - chemistry Endodeoxyribonucleases - metabolism Exodeoxyribonucleases - chemistry Exodeoxyribonucleases - metabolism Holliday Junction Resolvases - chemistry Holliday Junction Resolvases - metabolism Humans Mice Molecular Sequence Data Multifunctional Enzymes Protein Binding Protein Multimerization Protein Structure, Tertiary Pseudomonas aeruginosa - enzymology
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Summary:	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. [Display omitted] •Bacterial proteins comprising solely a VRR-Nuc domain are dimeric in solution•Bacterial VRR-Nuc domains act as Holliday-junction-resolving enzymes•A conserved helical insertion in the FAN1 VRR-Nuc domain prevents dimerization•FAN1 monomers cannot cleave Holliday junctions and instead cleave 5′ flap DNA The Fanconi anemia pathway is responsible for clearing DNA interstrand crosslinks that block DNA replication and transcription leading to genome instability. Here, Pennell et al. characterize the Fanconi-anemia-associated nuclease FAN1, comparing the structure and activity of its catalytic VRR-Nuc domain with prokaryotic examples. FAN1 is monomeric with 5′ flap specificity, whereas prokaryotic VRR-Nuc domains are dimeric Holliday-junction-resolving enzymes. FAN1 is proposed to contain a conserved helical insertion blocking dimer formation and consequently restricting substrate specificity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Co-first author
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2014.06.001