title: Loss of RMI2 Increases Genome Instability and Causes a Bloom-Like Syndrome.
abstract: Bloom syndrome is a recessive human genetic disorder with features of genome instability, growth deficiency and predisposition to cancer. The only known causative gene is the BLM helicase that is a member of a protein complex along with topoisomerase III alpha, RMI1 and 2, which maintains replication fork stability and dissolves double Holliday junctions to prevent genome instability. Here we report the identification of a second gene, RMI2, that is deleted in affected siblings with Bloom-like features. Cells from homozygous individuals exhibit elevated rates of sister chromatid exchange, anaphase DNA bridges and micronuclei. Similar genome and chromosome instability phenotypes are observed in independently derived RMI2 knockout cells. In both patient and knockout cell lines reduced localisation of BLM to ultra fine DNA bridges and FANCD2 at foci linking bridges are observed. Overall, loss of RMI2 produces a partially active BLM complex with mild features of Bloom syndrome.
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Parkville, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Damien F
authors.initials: DF
authors.lastname: Hudson
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Parkville, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Amor
authors.affiliation: Cytogenetics Laboratory, Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Parkville, Victoria, Australia.
authors.forename: Amber
authors.identifier: http://orcid.org/0000-0003-0802-1351
authors.initials: A
authors.lastname: Boys
authors.affiliation: Cytogenetics Laboratory, Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Parkville, Victoria, Australia.
authors.forename: Kathy
authors.initials: K
authors.lastname: Butler
authors.affiliation: Cytogenetics Laboratory, Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Parkville, Victoria, Australia.
authors.forename: Lorna
authors.initials: L
authors.lastname: Williams
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Parkville, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Parkville, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Paul
authors.identifier: http://orcid.org/0000-0001-5569-0609
authors.initials: P
authors.lastname: Kalitsis
mesh_terms: D001816:Bloom Syndrome / Q000150:complications / Q000235:genetics* / Q000473:pathology; D043171:Chromosomal Instability / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D045566:DNA, Cruciform / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics; D009369:Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D012854:Sister Chromatid Exchange / Q000235:genetics
chemical_list: D045566:DNA, Cruciform; D004268:DNA-Binding Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; C533196:RMI2 protein, human; D004265:DNA Helicases