title: Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability.
abstract: Mono-ubiquitination of Fancd2 is essential for repairing DNA interstrand cross-links (ICLs), but the underlying mechanisms are unclear. The Fan1 nuclease, also required for ICL repair, is recruited to ICLs by ubiquitinated (Ub) Fancd2. This could in principle explain how Ub-Fancd2 promotes ICL repair, but we show that recruitment of Fan1 by Ub-Fancd2 is dispensable for ICL repair. Instead, Fan1 recruitment--and activity--restrains DNA replication fork progression and prevents chromosome abnormalities from occurring when DNA replication forks stall, even in the absence of ICLs. Accordingly, Fan1 nuclease-defective knockin mice are cancer-prone. Moreover, we show that a Fan1 variant in high-risk pancreatic cancers abolishes recruitment by Ub-Fancd2 and causes genetic instability without affecting ICL repair. Therefore, Fan1 recruitment enables processing of stalled forks that is essential for genome stability and health.
authors.affiliation: Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lachaud
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors.forename: Alberto
authors.initials: A
authors.lastname: Moreno
authors.affiliation: School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Road, Glasgow G61 1QH, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchesi
authors.affiliation: Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Toth
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors.forename: J Julian
authors.initials: JJ
authors.lastname: Blow
authors.affiliation: Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, UK. j.rouse@dundee.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Rouse
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002869:Chromosome Aberrations; D004260:DNA Repair; D004261:DNA Replication; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D005090:Exodeoxyribonucleases; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D055879:Gene Knock-In Techniques; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D064251:Multifunctional Enzymes; D010190:Pancreatic Neoplasms / Q000235:genetics*; D054875:Ubiquitination
chemical_list: C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; D064251:Multifunctional Enzymes; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C000596972:Fan1 protein, mouse